Clinical Practice Guidelines for Treatment of Depression in Elderly Ajit Avasthi', Sandeep Grover2, Rahul Bharadwaj3 Introduction Elderly population is increasing throughout the world and India is no exception to this. In India, the past century has witnessed a decline in the birth rate and an improvement in life expectancy, with reduction in mortality amongst older persons. As a result of this, India's elderly population has increased from 12 million in 1901 to 57 million in 1990 and is expected to cross a 100 million in 2013. India is among the three countries (China, India and Indonesia) that are projected to have the largest number of old people in the year 2025. Further, the elderly population itself is getting older, with people over 80 years of age forming the fastest growing sub-group of the population in many countries. The psychological and physiological changes along with the social problems make elderly population very vulnerable to mental illnesses. Its detection demands vigilance and its diagnosis and management demand teamwork1 One of the common mental disorders seen in elderly population is depression.Though the incidence of depression is similar to that seen in younger adults; when it occurs it is more likely to be severe with higher risk of suicide and frequently requires hospital admission. It leads to more number of consultations with the treating agencies. It also leads to significant burden on families. Early recognition, diagnosis, and initiation of treatment for depression in older people present opportunities for improving their quality of life, preventing suffering or premature death, and maintaining optimal levels of function and independence. Earlier diagnosis and effective treatment of depression in old age can lead to significant reduction in morbidity, mortality due to suicide and medical illnesses and health care costs. The purpose of these guidelines is to present a framework for the evaluation, treatment, and followup of geriatric patient, who present with depression. To a large extent these guidelines are evidence based. Most of the data presented in these guidelines is from the western countries, as there is only meager research from India and other developing countries. For the purpose of review of literature, the studies which have been reviewed have been limited to the population aged 60 or more. We hope that these guidelines would help in facilitating proper management and avoiding unnecessary expense and inconvenience. However it is to be remembered that these guidelines are not a substitute for professional knowledge and clinical judgement. Why Depression is under-diagnosed in elderly Although the signs of depression in older people are mostly the same as for people in other age groups, there are a number of issues that can make it more difficult to detect. In comparison with younger people, older people under-report depressive symptoms and they may not acknowledge being sad, down or depressed. Whether this is due to age itself or a reflection of the generation in which they were raised, where stoicism was a virtue, is unknown. Often, common depressive symptoms (such as a loss of interest in life, lack of enjoyment in normal activities, apprehension, poor sleep, persistent thoughts of death, chronic unexplained pain, poor concentration or impaired memory) are incorrectly attributed to old age, dementia or poor health. Too frequently, family, friends and doctors see it that way as well with the result that depression in old age may go undetected and untreated for a long time. Other barriers to accurate diagnosis include confounding medical co-morbidity, patient stigmatization, which prevents effective health care seeking behavior and the accurate reporting of 1. Professor, 2. Assistant Professor, 3. Senior Resident - Department of Psychiatry PGIMER, Chandigarh
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symptoms. Among the atypical ways that depression may present in old age are the following: 1. Chronic unexplained physical symptoms: Many a times the elderly depressed subjects would present with a range of physical symptoms for which no adequate medical explanation can be found. Common symptoms include dizziness, chronic aches and pains, constipation, weight loss and insomnia. These patients would be less willing to mention psychologic symptoms and the symptoms of depression become apparent only on close questioning though the older person may not see it that way and deny that it could be the problem. In the extreme, the older person may become utterly convinced that they have an incurable illness and won't listen to reason. 2. Cognitive deficits: Depression in old age is often accompanied by cognitive changes but sometimes the memory impairment may seem to be the main problem and the older person and/ or their family become concerned that dementia is the problem. Treatment of the depression usually improves the memory, though sometimes it doesn't fully recover. 3. Behavioural changes: These can be quite varied and include symptoms suggestive of agoraphobia in which the older p jrson becomes housebound with fear, refuses to eat, shoplifts, 'accidentally' overdoses, lives in squalor, or abuses alcohol. At times depressed elderly would appear preoccupied with changing their will, would give away personal possessions, would talk about death, or takes an unprecedented interest in firearms. 4. Anxiety and Worries: Worry and nervous tension (as opposed to specific anxiety syndromes, such as panic disorder) are common presentations of depression in older people. 5. Irritability/dysphoria and agitation: At times the elderly depressed subjects may deny depressed mood or sadness, but would complaint of irritability, would be agitated and would have difficulty in coping with situation2. Phenomenology of elderly depression Clinical features normally regarded as more common in elderly depressed patients include: neurovegetative symptomatology, somatic preoccupation, agitation, forgetfulness and delusions. These stereotypic descriptions of depression in later life derive, in the main, from the study of inpatients and may reflect illness severity. Blazer et al3, using an approach, which controlled for symptoms that may increase fortuitously with age, found: (a) Older depressed subjects reported more somatic symptoms. (b) Older people had more thoughts about death and had a greater preoccupation with the wish to die than younger people, although not significantly so. (c) Surprisingly, it was the younger rather than the older people with depression who reported more memory problems. (d) There was no support for the notion of masked depression in the elderly. Musetti et al4 could find no symptoms, which reliably differentiated older community dwelling,patients with major depression from younger ones. Against expectations, the group over 65 years, exhibited more retardation than agitation. In terms of clinical presentation, the adage depression is depression at any age' has some truth to it. However, the pathoplastic influences of age and ageing alter the presentation of depression among the elderly. Some of the other studies have been reviewed in table-1. Factors which may alter or obscure presentation5 • Overlap of physical and somatic psychiatric symptoms • Reduced expression of sadness • Somatisation or disproportionate complaints associated with physical disorder • Neurotic symptoms of recent onset (52)
Medically 'trivial' deliberate self-harm Pseudodementia Depression superimposed upon dementia Behavioural disorder Accentuation of abnormal personality traits Late-onset alcohol dependency syndrome
Table-1: Studies In the phenomenology of elderly depression TITLE OF STUDY Depression in later life. A compar, ;on of symptoms and risk factors in early and late onset cases
Behavioral phenomenology in Alzheimer's disease, frontotemporal dementia, and late-life depression: a retrospective analysis. Late-life depression: the differences between early- and late-onset illness in a community-based sample.
A comparison of earlyonset and late-onset depressive illness in the elderly.
Clinical and p'nenomenological comparisons of lateonset and early-onset depression
AUTHOR, YEAR Baldwin RC et al, 1995
RESULTS
CONCLUSION
Anxiety item scores of the Hamilton Vascular disease is Depression Rating Scale were associated with latesignificantly higher in those with an onset depression. early onset. Otherwise symptoms differed little. Heritability was greater in the early-onset group. There was a striking association of vascular disease and/or risk with late-onset patients Swartz JR Results indicated that Alzheimer's Better definition of the Disease, Fronto-Temporal Dementia longitudinal course of. etal, 1997 and Late Life Psychotic Depression noncognitive were distinguished retrospectively by behavioral symptoms the SCAN without using cognitive data. in psychiatric disorders ). A subset of 14 SCAN item group will be valuable for symptoms collectively classified diagnosis. subjects in each diagnostic category. Janssen J Those with Late Onset Depression were All patients with lateolder, and more often widowed. Family life depression et al, 2006 psychiatric history, vascular pathology, deserve a diagnostic and stressful early and late life events work-up of both did not differ between groups. Early psychosocial and Onset Depression (65 years have been reported to use at least 5 medications per week; in a nursing home setting, residents have been reported to receive an average of 7 or 8 medications per month82 83. Some of the medications used for treatment of physical comorbidities by the elderly are the potential preventable causes of depressive symptoms. Table -2 provides a list of drugs which have been associated with development of depression8485.The amount of research concerning these associations varies, with extensive study of some agents (e.g., a blockers) and data on others limited primarily to case reports and case series. Reports contradicting some of these associations are also available. Alcohol Use: Data from community-based epidemiologic studies consistently show that in elderly depressed subjects, the prevalence of alcohol use is three to four times greater than in elderly nondepressed subjects. In clinical samples of elderly inpatients with major depression, the prevalence of alcohol use disorders appears to be in the 15%-30% range8667, and only a small proportion abuse other substances in addition to alcohol86. However the relationship between alcohol abuse and depression is not clear. The problem in establishing the relationship between the two remains because in many patients with comorbid alcohol use disorder and depressive disorder, it is often difficult to tease out which condition predated the other8889. It has been suggested that depression can predispose to alcohol use, and alcohol use can predispose to depression. Anxiety and Geriatric Depression: Anxiety is a frequent concomitant of depression. From a theoretical perspective, in some patients with comorbid depressive and anxiety disorders, these conditions may represent two artifactual subcategories of symptoms of a single disorder. The literature suggests that generalized anxiety disorder and possibly phobias comprise the majority of comorbid anxiety disorders in geriatric major depression9092. The symptom of psychic or somatic anxiety appears to be fairly common in elderly patients with major depression, both in psychiatric and primary care samples9396. Diagnoses of subtypes of depression in a large community population study support the view that anxiety is common in depressed patients, whether or not they meet criteria for MDD96. In a mixed sample of psychiatric and primary care patients, 23% of elderly patients with major depression had a current anxiety disorder and 35% had a lifetime anxiety disorder94. Nutritional deficiencies: Compared to young adults, elderly subjects are more prone to develop nutritional deficiencies. Low folate levels have been found in many studies of depressive patients. Studies have reported folate deficiency in 15-38% of depressive patients. Lower serum folate concentrations have also been linked to severity of depression. Low plasma folate and raised homocysteine have been linked to heart disease and strokes in a very large number of studies. There is also a link between depression, heart disease and increased risk of dying after a cardiac infarction97. These connections provide a plausible reason for these two groups of serious disease to be connected. Vitamin B12 levels are also often low in depression. The American Women's Health and Ageing Study98 reported functional vitamin B12 deficiency to be commoner among depressive than among non-depressive elderly women. Metabolically significant vitamin B12 deficiency was present in 17% of mildly depressed subjects and in 27% of severely depressed subjects in this community based study. Subjects with vitamin B12 deficiency (serum levels < 148 pmol/l or 200 pg/ml) were more than twice as likely as nondeficient subjects to be depressed after adjustment for other relevant factors. In another study it has been found that subjects with vitamin B12 deficiency were 70% more likely to have severe depressive disorder than subjects without deficiency99. Other factors: Other factors which have been postulated to be risk factors for depression in old age include pain, visual impairment, loneliness, lack of social support, negative life events and perceived inadequacy of care, subjective memory impairment, previous anxiety and somatoform disorders100'101.
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Murphy102 reported the importance of recent life events in development of depression in elderly. She found that depressed elderly subjects were more likely than normal subjects to have experienced a severe life event in the previous year. Further, persistent social difficulties like financial and familial problems have been linked to depression. Living alone has also been associated with increased risk of depression in old age. Management of depression Antidepressants: Although depression is equally common in old and young adults, most of the drug trials exclude elderly subjects. In addition to the exclusion of elderly, most of the drug trials also exclude subjects with medical comorbidity, which is a rule rather than exception in elderly subjects. Prior to 1995 there were no studies or occasional studies that evaluated the use of antidepressants in elderly. But fortunately in the last 10 years many studies of use of antidepressants have been reported. In the following section we would discuss the issues of pharmacokinetics & pharmacodynamics, drug interaction, side effects and efficacy in relation to elderly. However, as it is not possible to discuss each drug specifically in relation to elderly subjects, where ever data is lacking the general principles.for prescription for elderly should be followed. Pharmacokinetics of antidepressants in elderly: As the subjects grow older the efficiency of the processes controlling drug absorption, distribution, metabolism and elimination undergo substantial change as shown in table-3103'105. Table-3: Pharmacokinetic changes Absorption • Amount of saliva • Gastric pH • Gastric acid secretion • Gastrointestinal surface area • Gastrointestinal motility • Active transport mechanism • Gastrointestinal blood flow • Gastric dopa • Decarboxylase Distribution • renal blood flow • hepatic blood flow • body water • volume of distribution for water soluble drugs • body fat • volume of distribution for lipidsoluble drugs • serum albumin levels
Metabolism • microsomal hepatic oxidation
occurring with aging • Decrease in rate and/or completeness of absorption of orally administered drugs • Decreased absorption of nutrients and vitamins • Absorption of most of the psychotropic are not affected as most of them are lipid soluble and diffuse passively
• Lower elimination of drugs which are partially or completely eliminated by kidneys • Decrease hepatic clearance of drugs and increased plasma concentration • Proportionate increase in volume of distribution of water soluble drugs • Proportionate increase in volume of distribution of lipid soluble drugs i.e., most antidepressants • Increase in half life of lipid soluble drugs • Plasma protein binding of most of the antidepressants decreases • Increase in free plasma concentration of drugs • • • • •
• clearance • steady state levels • half lives • level of active metabolites • first pass metabolism
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Understanding and knowledge of these facts is very important in prescribing antidepressants in elderly specially those on more than one drug. For example due to disease and aging physiology, renal elimination and liver metabolism of drugs may be impaired in many elderly patients. These alterations in pharmacokinetics in the elderly may contribute to increase in volume of distribution, decrease in elimination, longer half life etc. Further it has also been seen that the pharmacokinetic changes resulting from aging often lead to higher and more variable plasma drug concentrations. Pharmacokinetic studies of antidepressants in elderly: As discussed above, aging leads to changes in pharmacokinetics of antidepressants, and most of the studies as shown in table-4 with newer antidepressants also confirm these findings.
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10-40
Citalopram
Citalopram
Fluoxetine Fluvoxamine Fluvoxamine Sertraline
Sertraline Paroxetine Bupropion
Reboxetine Nefazodone
Venlafaxine
Mirtazapine
Gutierrez & Abramowitz, 2000
F o g l i a e t a l , 1997 Fredericson Overo et al, 1985
Bergstromet al, 1983 DeVries et al, 1993
Physician desk, 1999 Ronfeldetal, 1997
Ronfeldetal 1997 K a y e e t a l , 1989
Sweet e t a l 1995
Bergmann et al, 2000
Barbhaiya, e t a l , 1995, 1996
Klamerus, e t a l , 1992
Remeron, 1999 Single dose
150
300600
4
100300
200 20
50-200
40 100
20
Dose mg/d
Drug
Author
18V
24V
12V
6
22 V 14pts
22 V
13P
11 P
24 V
Sample size
Table-4; Pharmacokinetic trials of Antidepressants in elderly
60-80
65-78
81
63-76
>65
>65
65-77 63-77
73-90
Mean Age
5
8
1
9
21
28
Study duration in days 35
Concentration higher and longer half -life in elderiy men and women compared to young men Recommendation: Use cautiously in elderly
Half life longer in elderly women 50% increase of metabolites in elderly women Recommendation: Use half the initial dose in elderly 24 % increase in steady-state half life in elderly 14% increase of metabolites 23% reduced clearance Recommendation: Dose adjustment based on age may not necessary
Clearance reduced; appropriate starting dose 4 mg/d.
Clearance reduced by 50 % Concentration higher in elderly men and women compared to young men but similar to young women Recommendation: No specific dose change Metabolism slowed in elderiy males. Steady state plasma concentration higher Recommendation: lower initial dose Decreased clearance and prolonged half-life in elderly (mean 34.2 hrs compared to 14 hrs in young adults) Elderly at risk for accumulation of bupropion and its metabolites. Recommendation: Initial dose should be reduced by atleast 25 %
AUC increased by 30 -50 % in single dose study, and 23-30% in multiple dose study Steady state concentration increased, clearance decreased, longer half life Plasma concentration of elderly receiving 20 mg/day equal to 40 mg/day in young adults Recommendation: decreased initial dose No change Similar AUC and half life as in young adults
3 0 % increase in elimination half-life.
Outcome
Pharmacodynamic Changes: Besides the pharmacokinetic changes, there is a natural and progressive loss of function of body tissues at the cellular level which also influences the pharmacodynamic activities, especially in the central nervous system. The altered responses to drugs in the elderly could be due to several factors including age-related changes in drug-receptor interactions, receptor-membrane interactions, postreceptor events, structural changes in organs or tissues, and altered homeostatic functions. Further, homeostatic mechanisms that function via central and peripheral feedback mechanisms are altered in the elderly. Postural hypotension often occurs. The baroreflex is blunted, as is the reflex tachycardia that occurs in the upright position. There is increased susceptibility to many commonly used drugs. These include benzodiazapines, antidepressants, neuroleptics, which show an increased penetration into the aged central nervous system." le response of older patients to drugs in general is very variable; therefore, all drugs should be used appropriately and with caution in these subjects104. Table-5 summarizes some of the important pharmacokinetic and pharmacodynamic issues to be remembered while prescribing antidepressants in elderly. The principle of "Start low and go slow" should be followed. Table-5: Points to remember for prescription of antidepressants in elderly 1.
Elderly are more sensitive to a given dn.g concentration
2. The body organs of elderly have decreased capacity to adapt 3. There is progressive loss of functional body tissues at the cellular level 4. Starting dose of an antidepressant must be lower (one third to half) for elderly compared to the starting dose used in young adults 5. The half life of most of the antidepressants increases 6. Elderly require longer duration to achieve a steady plasma state 7. Side effects related to dose or concentration will take longer to resolve 8. Homeostatic mechanisms that function via central and peripheral feedback mechanisms are altered in the elderly and make them more susceptible to side effects Drug interactions Drug-drug interactions are more likely in the elderiy because they tend to use multiple medications. Most studies of community-dwelling elderly suggest that the average older person uses between two •ind six prescribed medications and one and three nonprescription medications on a routine basis120. Many authors by using combinatorial analysis have shown that there is a theoretical probability of greater than 50% for having a drug interaction when a patient is receiving five medications, and this probability increases to 100% when seven drugs are used. When risk probabilities were determined
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in actual patients, these theoretical probabilities were very close to actual data too121. Besides the use of nonprescription medication, another important reason for use of multiple medications is introduction of and many of newer agents have made significant impact on management of various illnesses122. But the foremost important reason of use of multiple medications, is seeking treatment from multiple physicians for the same or multiple illnesses. Duplication of therapies or prescribing counter-acting drugs can occur when two or more prescribers do not know what the others are doing. It is common for prescribers to have inaccurate information about the drugs their patients are taking122. It is easy to overlook a potential drug interaction, particularly those that negate a therapeutic effect, such as those seen with enhanced drug metabolism or pharmacodynamic antagonism. Often the poor effectiveness of a drug is ascribed to worsening disease or poor medication adherence rather than a possible drug interaction. All clinicians must seek to identify these types of drug-related problems. Even if an interaction has not been reported in the literature that does not mean that it cannot occur. Hence, the number of drugs used to treat elderly patients must be minimized to reduce the incidence of adverse reactions, potential drug-drug interactions, and adherence difficulties while at the same time minimizing costs associated to with pharmacotherapy. To avoid drug interactions it is imperative that a thorough medication history be taken at each visit and the history must include history of use of nonprescription drugs and herbal medications. Patients should be instructed to bring all their medications, including nonprescription and herbal products, to their psychiatrist for review. Now a day's many readymade websites and other computer applications are available to screen for potential drug-drug interactions122. The most clinically significant drug interactions are often related to inhibition or induction of CYP450 enzymes. Hence, it is important to know the metabolic pathways of the medications patients are taking to help prevent such interactions from occurring. Secondary pharmacological actions of drugs and their impact on the effectiveness of other medications patients are using must also be considered. Table-6 shows the common CyP 450 enzymatic pathways followed by antidepressants along with other substrates and inhibitors of these pathways122125. Another important site of drug interaction for antidepressants is plasma protient binding. Most of the antidepressant (except venlafaxine) has high plasma protein binding and the drugs which can displace them from the binding sites (e.g., anticoagulants, antiarrhythmic agents) should be avoided or minimized.
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Table-6: Antidepressants, other medications and CYP enzymes CyP 2D6
CyP 3A3/4
Amitriptyline Clozapine Codeine Desimipramine Encainide Flecainide Fluoxetine Haloperidol Imipramine Maprotiline Metoprolol Mexiletine Nortriptyline Paroxetine Perphenazine Phenformine Propafenone Propafenone Propranolol Risperidone Sertraline Thioridazine Timolol Trazadone Venlafaxine Zuclopenthixol
Acetaminophen Alprazolam Amitriptyline Astemizole Carbamazepine Cisapride Clomi' ramine Clozapine Cortisol Cyclosporine Dexamethasone Diltiazem Erythromycin Ethinyl estradiol Imipramine Lidocaine Midazolam Nefazodone Nifedipine Propafenone Quinidine Sertraline Tamoxifen Terfenadine Triazolam Verapamil Vinblastine
CyP1A2 ;Substrates Acetaminophen Amitriptyline Caffeine Clomipramine Clozapine Clozapine Fluvoxamine Haloperidol Imipramine Phenacetin Propranolol Tacrine Theophylline Verapamil
CyPC9
CyP 2C19
Diclofenac Ibuprofen Mefenemic acid Naproxen Phenytoin Piroxicam Tolbutamide Warfarin
Diazepam Hexobarbital Imipramine Mephenytoin Omeprazole Propranolol
Sulfonamides
Quinidine Fluoxetine Norfluoxetine Paroxetine
Inhibitors Quinidine Fluoxetine Norfluoxetine Paroxetine Bupropion Terbinafine Diphenhydramine
Ketoconazole Itraconazole Grapejucie Erythromycin Clarithromycin Nefazodone Fluvoxamine Ritonavir
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Table-7: Monitor or avoid following combinations in elderly Absolutely contraindica ted MAOIs other TCAs
Avoid if possible
Fluoxetine
MAOIs
TCAs, Phenytoin, Cisapride, codeine, Flecainide, propafenone
Sertraline
MAOIs
Codeine Cisapride
Paroxetine
MAOIs
TCAs, codeine, flecainide, propafenone
Citalopram
MAOIs
Fluvoxamine
MAOIs cisapride
TCAs, Clozapine haloperidol, diazepam
Bupropion
MAOIs
Venlafaxine
MAOIs
Nefazodone
MAOIs cisapride MAOIs
All agents that lower the seizure threshold (eg antipsychotics antidepressants theophylline systemic steroids) Norepinephrine agonists (when high doses of venlafaxine are prescribed) Desipramine, alprazolam, triazolam Diazepam
Agent
TCAs
Mirtazapine
Inhibitors of CyP-450 anticholinergic agents
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Carefully monitor
Antihypertensive (eg guanethidine), Thyroid drugs, Sedatives/hypnotics Sympathomimetic drugs (e.g., epinephrine) Warfarin, Haloperidol, Clozapine alprazolam, triazolam, carbamazepine beta blockers, cyclobenzaprine, lithium, serotonergic drugs (eg tryptophan dextromethorphan) TCAs, haloperidol, warfarin .cimetidine, diazepam, tolbutamide .lithium serotonergic drugs Haloperidol, Warfarin, lithium, digoxin, procyclidine, phenobarbital, cimetidine theophylline, phenytoin .serotonergic drugs TCAs, metoprolol .cimetidine lithium,serotonergic drugs Warfarin, alprazolam, midazolam, triazolam, theophylline, lithium serotonergic drugs Levodopa
Cimetidine, serotonergic agents
Digoxin, haloperidol, propranolol, serotonergic agents Serotonergic drugs, antihistamines alphal-adrenergic antagonists (eg doxazosin mesylate) , alcohol
Drug Fluoxetine
Citalopram
Venlafaxine
Mirtazapme
Interactions • Severe reaction with MAO inhibitors (serotonin syndrome) • Seizure risk when given concurrently with drugs that lower seizure threshold • Increased risk of serotonin syndrome if mixed with other SSRIs, amphetamines, sumatriptan, ritonavir, tramadol, venlafaxine • May increase serum levels of benzodiazepines, beta-blockers (except atenolol or nadolol), carbamazepine, dextromethorphan, digoxin, haloperidol, 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (lovastatin and simvastatin), phenytoin • May also decrease levels of carbamazepine, phenobarbital, phenytoin, rifampcin • Concurrent use with lithium increases risk of neurotoxicity from increased lithium levels • Both increased and decreased lithium levels have been reported with fluoxetine • Risk of hyponatremia with concurrent use of loop diuretics (bumetanide, furosemide, torsemide) • May increase hypoprothrombmemic response to warfarin • Increased CNS depression with alcohol • Increased CNS depression may result from concurrent use with valerian, St. John's wort, kava kava, gotu kola • Increased risk of serotonin syndrome if mixed with buspirone, MAO inhibitors, sumatriptan, tramadol • Increased serum levels if given with cimetidine • Increased serum levels if given with nefazodone. erythromycin, grapefruit juice, Mc. • Increased risk of bleeding if given concurrently with NSAIDs • Increased risk of serotonin syndrome if mixed with buspirone, MAO inhibitors, meperidine, m rtazapme, nefazodone, selegiline, sumatriptan, naratriptan, rizatriptan, zolmitriptan, sbutramine, SSRIs, trazodone, tricyclic antidepressants • May increase hypoprothrombmemic response to warfarin • Ircrer.sed risk of seizures with clozapine • Increased serum levels if given with amiodarone, cimetidine, clarithromycin, erythromycin, diltiazem. disulfiram, fluoxetine, grapefruit juice, indinavir, itraconazole, ketoconazole, metronidazole ritonavir • Einzyme inducers increase metabolism of venlafaxine (decreasing effect): phenobarbital, carbamazepine, phenytoin, rifampcin. • 'ncreases levels of haloperidol • ncreased CNS depression with alcohol • Increased CNS depression and/or serotonin syndrome may result from concurrent use with valerian, St. John's wort, kava kava, S-Adenosyl L-Methionine (SAM-e). tryptophan • Decreases antihypertensive effect of clonidine • Increases CNS depression with barbiturates, benzodiazepines, narcotic analgesics, alcohol, otrnr sedatives • Enzyme >iducers increase metabolism of mirtazapine (decreasing effect): barbiturates, caroamazepine, phenytoin. rifampin • Avoid concurrent use with MAO inhibitors: can be fatal if given within 14 days • Possible serotonin syndrome with sibutramine and selegiline • Increased CNS depression may result from concurrent use with alcohol, valerian, St. John's wort, SAMe, kava kava
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Side effects of antidepressants Elderly people are generally more susceptible to side effects, and due to the same the newer antidepressants are preferred. Besides the common side effects seen with antidepressants elderly subjects are particularly prone to certain side effects like orthostatic hypotension and falls, hyponatremia, Cardiac side effects, etc. In this section we would limit ourselves to description of side effects which are of concern in old age. TCAs: The side effects of TCAs result from their blockade of central and peripheral cholinergic receptors (dry mouth, blurred vision, constipation, urinary hesitancy or retention, cognitive impairment, tachycardia), histaminergic receptors (sedation, weight gain) and a-adrenergic receptors (orthostatic hypotension). Among the cyclic compounds, nortriptyline and desipramine are less likely to induce these effects than otherTCAs and are therefore preferred in elderly patients. Of the TCAs, nortriptyline is the least likely to cause orthostatic hypotension. It has been studied in elderly depressed patients and has been reported to be well tolerated by "young old" individuals who are medically stable and who do not have dementia. Nortriptyline has been found to be less well tolerated in very old or frail nursing home residents, patients who have had a stroke and people who are medically ill. All TCAs, including nortriptyline, slow cardiac conduction and therefore are not safe for patients with bundle branch block.TCAs also have significant antiarrhythmic activity resembling that of class 1 antiarrhythmic compounds such as quinidine. Class 1 antiarrhythmics increase the risk of death in patients with moderate to severe ischemic heart disease, and therefore TCAs should not be given to these patients123128129. SSRIs: With the exception of paroxetine, which has a moderate effect on cholinergic receptors (and therefore the potential for anticholinergic side effects), the SSRIs have little affinity for adrenergic, histaminergic, cholinergic or dopaminergic receptors.The side effects of SSRIs, which primarily reflect central and peripheral serotonin reuptake inhibition, include gastrointestinal upset (nausea, anorexia, frequent and loose stools), central nervous system dysfunction (insomnia, sedation, apathy, nervousness, restlessness, dizziness, tremor and headaches) and sexual dysfunction (decreased libido, anorgasmia, delayed ejaculation and impotence).SSRIs can also induce postural instability in older people, increasing the risk of falls123128129. An infrequent but potentially dangerous side effect is the syndrome of inappropriate secretion of antidiuretic hormone and hyponatremia. Over the years many cases of hyponatremia, some of which are compatible with Syndrome of Inappropriate AntiDiuretic Hormone (SIADH) secretion, have been reported with the use of SSRIs, especially in elderly population. Most reports have implicated fluoxetine but reports with sertraline, paroxetine, citalopram, fluvoxamine, escitalopram are also available130131.The risk in elderly seems to be greatest during the first few weeks of treatment, which increases further with increasing age132. Females and patients with low body weight are reported to be at higher risk. Besides these the risk of SIADH is more in subjects who receive diuretics, antipsychotics, narcotic and oral hypoglycaemic agents along with (71)
SSRIs133'136. In a review of case reports associated with SSRIs, the median time of onset of hyponatremia is reported to be 13 days. It has also been found that in about two-third of cases rechallenge with the same SSRI resulted in recurrence of hyponatremia13'. Monitoring of electrolyte levels in elderly, especially during first 2 to 4 weeks of therapy may be worth while. In healthy volunteers, SSRIs produce no significant cardiac effects and do not produce postural hypotension, although their use in patients with cardiac disease has not been well studied. In contrast to TCAs and firstgeneration MAOIs, SSRIs taken alone in an overdose do not cause death. Side effects tend to be dose related and are often transient. Patients who cannot tolerate one SSRI may well be able to tolerate another. There are also reports of bleeding complications with SSRIs. Although the side effects of SSRIs and TCAs differ and SSRIs are the safer of the two drugs, it has not been established whether elderly people tolerate SSRIs better than secondary amine TCAs. Among the SSRIs, prescribing fluoxetine due to its longer half life is potentially more problematic in elderly people than the other SSRIs, which have half lives of 26 hours or less and no clinically active metabolites. Further as discussed above, SSRIs inhibit isoenzymes of the hepatic P-450 cytochrome system, which is involved in the metabolism of a large number of drugs. Although SSRIs are not the only psychotropics with this property, the potency of their inhibition and their potential to increase the plasma concentration of a variety of medications has led to concern. Particular caution should be exercised when any SSRI is prescribed with drugs that have a narrow therapeutic window (margin between a therapeutic dose and a toxic dose), such as tricyclic antidepressants, antipsychotics, theophylline, phenytoin, carbamazepine and tolbutamide.The administration of an SSRI with the antihistamine terfenadine or astemizole is contraindicated because of the risk of fatal ventricular arrhythmias resulting from P-450 3A4 inhibition. Also, SSRIs should be administered with caution, if at all, to patients taking type 1C antiarrhythmics (encainide, flecainide, propafenone). Like TCAs, SSRIs are highly protein bound and therefore have the ability to displace and thereby enhance the effect of other protein bound drugs (e.g., warfarin and digoxin). The SSRIs have a flat dose-response curve. This means that, for the majority of patients, increasing the amount beyond the minimum effective dose does not increase efficacy but can cause more side effects. Consistent with the flat dose-response curve, there is no relation between plasma SSRI concentrations and clinical response123128129. Other antidepressants: Trazodone has a strong sedating effect that can result in daytime drowsiness, falls and impaired cognitive functioning. It can also cause orthostatic hypotension (with the risk of falls) and ventricular arrhythmias. These factors can limit its usefulness as an antidepressant in late life. The most common side effects associated with nefazodone include nausea, drowsiness, dry moi-ih} dizziness, constipation and asthenia. At higher doses, it may impair cognitive and psychomotor functioning in the elderly. Nefazodone does not cause sexual dysfunction, and it does not appear to have clinically significant cardiovascular effects. It is a potent inhibitor of P-450 3A4. Consequently, it should not be used with terfenadine or astemizole, and caution should be exercised when it is (72)
administered with other drugs metabolized by this isoenzyme123128129. The most common side effects of venlafaxine are nausea (which usually resolves rapidly), somnolence, dry mouth, dizziness, nervousness, constipation, sexual dysfunction, sweating, asthenia and anorexia. Blood pressure monitoring is recommended before and during venlafaxine treatment because a small number of patients experience modest dose-dependent elevations of blood pressure. Venlafaxine is only a weak inhibitor of P-450 2D6 and is less likely than paroxetine or fluoxetine to interact with drugs metabolized by this isoenzyme. Unlike SSRIs, venlafaxine does not have a flat dose-response curve, and higher doses are associated with better responses123128129. Studies of antidepressants in old age depression Although depression is equally common in old and young adults, most of the drug trials exclude elderly subjects. In addition to the exclusion of elderly, most of the drug trials also exclude subjects with medical comorbidity, which is a rule rather than exception in elderly subjects. Hence the results of drug trials done in young adults can't be generalized to elderly. Prior to 1995 there were occasional studies which evaluated the use of antidepressants in elderly. But fortunately in the last 10 years many studies have evaluated the use of antidepressants in the elderly. These studies can be broadly classified as: Noncomparative studies, comparative studies using either placebo or another antidepressant or both and meta-analyses of the above studies. In the following section we would discuss the antidepressant trials done specifically in elderly subjects. Noncomparative studies Antidepressant trials without drug comparisons are shown in Table-9. These studies have evaluated nortriptyline, SSRIs, Venlafaxine, reboxetine andTianeptine in major depression in both inpatient and outpatient setting. Some studies have also evaluated the use of antidepressants in minor depression and dysthymia. Some studies show more than one drug listed, but in these cases the drugs were not actually compared with each other but were given consecutively. Overall, these noncomparative studies support the efficacy of antidepressants in the elderly and suggest those antidepressants are well tolerated. Four studies focused on outpatients with dysthymia or minor depression and all reported the efficacy of an SSRI or reboxetine. Relapse and recurrence was common in these reports, but switching antidepressant (e.g., nortriptyline for SSRI nonresponders; MAO inhibitors for TCA nonresponders) was often effective in producing a response. Psychotic and medically ill patients had an overall poorer response to antidepressants than outpatients. Studies evaluating the antidepressants for longer duration have shown that they are reasonably effective in preventing relapse. Successful therapeutic augmentation of antidepressant response was reported for methylphenidate, and estrogen replacement.
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Lavretsky & Kumar 2001 Arranz & Ros 1997 Rosen et al 2000
Dew et al 1997
Sertraline
MPHD Citalopram Sertraline
Nortriptyline Phenelzine ECT Nortriptyline, Phenelzine, Lithium Nortriptyline
Flint and Rifat 1996
Flint and Rifat 1997a, b
84 OP
Nortriptyline, Phenelzine, lithium, ECT
Flint, 1997c, 1997
50-200
25 15-39
74 OP
Nortriptyline, Phenelzine
1437 OP 12
10 OP
95
99 OP
101
minor dep NH DSMIV
DSMIV
SADS-L RDC
DSM-III-R
DSM-III-R
Nonpsych otic; unipolar.
83.2
68
79.8
67.1
73.9
73.9
73.9
72.9
72.9
DSMIII-R
38 OP
Flint and Rifat 2001
74.4
DSM-IIIR
SADS-L
Mean Age 76.8
21
Nortriptyline, Phenelzine Nortriptyline, Phenelzine
Flint and Rifat 1999 Flint and Ritat 2000
159
Nortriptyline
Little, 1998
78.7
Tabla-9: Noncomparativa effectlvenaaa atudlea of antidepreaaanta D o * * in Sample Drug mg/d Dlagnosti Author mg/d aize c criteria Nortriptyline DSM-IV 54 10 Weintraub, 2001 IP/OP
6 weeks
8 weeks
8 weeks
18 weeks
14 weeks
14 weeks
2 years
4 years
208 weeks
2 years
26 weeks
Study duration 2-8 weeks
HAM-D, GAS
MADRS
HAM-D
HAM-D
HAD
HAM-D
HAM-D
HAM-D HAM-A
HAM-D MMSE, LE HAM-D
Minor depression in NH: 75% remission.
History and EEG sleep charac-teristics can predict response to treatment. Rapid response associated with low stress prior to onset, late onset age, milder Sx, and higher % REM and delta sleep. Significant augmentation of citalopram effect in 8/10 Effective, well tolerated.
Maintenance treatment with full-dose antidepressants resulted in 74% cumulative probability of surviving without relapse or recurrence. Anxious patients had a higher relapse rate over a 2- year follow-up period. Phenelzine effective, but slower in NT nonrespondeis; poor response to ECT in treatment failures Sequential treatment. Anxious patients less responsive lo treatment.
Maintenance treatment with full-dose antidepressants resulted in 70% cumulative probability of surviving without relapse or recurrence Responders to 1st drug had 18% relapse; those who needed a second drug after failing the first had 67% relapse rate.
11.9% did not experience remission and 18.4% were treatment resistant. Cumulative probability of recurrence 60.6%.
70% response to addition or substitution of NT in SSRI nonresponders
Clinical evaluation HAM-D
Outcome
Rating seal**
25
Fluoxetine
Fluoxetine
Venlafaxine
Venlafaxine
Venlalaxine
Reboxetine Reboxetine
Tianepline
Orengo et al 1996
Devanand et al 1997
Dierick, 1996
Khanetal 1995
Amore etal 1997
Aguglia, 2000 Andreoli et al 1999 Saiz-Ruiz et al 1998 Bodani et al 1999 Alexopoulos, 1996
75-225
50-150
20
20-60
2TRD 86 IP/OP
63 OP
160 12
28 OP
58 OP
116 OP
29 OP
31 IP
DSM-IV DSM-IV
DSM-IV
DSMlll-R
Dysthymia DSMIII-R
DSMKI-R Dysthymia DSM lll-R
Dysthymia & minor dep; DSM-HIR; DSM-IV SADS-L RDC
>65
65-94 75-87
>65
71.0
>65
67.5
71.8
67.2
>60
71
3 months
1 year 4 weeks
24 months
12 months
52 weeks
13 weeks
CGI, MMSE MADRAS
CGI, HAM-D CGI, HAM-D
CGI, SCL, QOL HAM-D
HAM-D, CGI.CDRS HAM-D, BPRS, MMSE HAM-D, Cornell Dysthymia, CGI MADRS, CGI
13 months 10 months
MADRS
HAM-D
HSCL. HAM-D
6 weeks
12 weeks
11 weeks
Effective and well tolerated.
Safe and effective except for more severely depressed patients; good prophylactic efficacy 95% of the subjects improved by 1 year 7 improved; tachycardia in 5.
Effective antidepressant
Effective for 2/3 of subjects by 2 months.
12 responders among patients with dysthymic disorder; 6 relapsed over next 24 weeks.
Moderate improvement; well tolerated.
62% improvement following 1 night sleep deprivation. Responders had low RBC count, lower plasmafree tryptophan. Effective fcr dysthymia; well tolerated.
Paroxetine showed moderate benefit; superior to psychotherapy.
Effective for treatment resistant depression. Recovery rate similar to that in younger RDC; 74.9 18.2 HAM-D, depressed patients; late age of'onset predicts moderate, CSDD, months slow recovery severe, & GDS, MMSE, psychotic Mattis patients. Dementia CGI - Clinical Global Impression Scale; CSDD- Cornell Scale for Depression in Dementia; DSMIII-R- Diagnostic and Statistical Manual Revised -III edition; DSMIVDiagnostic and Statistical Manual -IV edition; GAS- Global Assesment Scale; GDS- Geriatric Depression Scale; HAM-A- Hamilton Rating Scale for Anxiety; HAM-DHamilton Rating Scale for Depression; IP- inpatients; MADRS- Montgomery-Asberg Depression Rating Scale; Mattis-Mattis Dementia Rating Scale; MMSE- Mini Mental State Exam; NH- Nursing home patients; OP outpatients; QOL- Quality of life; RDC- Research Diagnostic Criteria: SADS-L- Schedule for Affective Disorders and Schizophrenia—Lifetime; TRD- treatment resistant depression
Dexamethasone All antidepressants
4-8
Fluoxetine
"NobleFeFal 1'996 23 OP
16
Fluoxetine
Mentre et al 1998
20
130P
Paroxetine
4150P
Bumpetal 1997
10-40
Paroxetine
Williams et al 2000
Placebo controlled trials Over the years many placebo control trials have been conducted in elderly subjects, but some have limitations in the form of shorter duration, not reporting diagnostic criteria and outcome. Here we review control trials with a placebo control arm of minimum 4 weeks duration involving subjects more than 60 years of age with a diagnosis of major depressive disorder or minor depression. These studies are shown in table-10. From the table it is evident that there are differences across studies in diagnostic schemes, entry criteria, and the subject population's location, in addition to methodological variations in dosing strategies and placebo lead-in periods and many scales have been used to measure outcomes. Most of these studies have involved fluoxetine, nortriptyline and sertraline. Some studies have also compared moclobamide and methylphenidate. Most of these studies which have evaluated outcome in terms of efficacy report that antidepressants are equal or better than placebo but antidepressants have higher incidence of side effects. Methylphenidate has been shown to be superior to placebo in medically compromised subjects. Studies with longer duration also have shown that stoppage of antidepressants lead to relapse of depressive symptoms.
Cont... (76)
Fluoxetine
20 23.3 -26.4
Fluoxetine
Fluoxetine
Paroxetine
Koran et al, 1995 Burrows et al
20
20
Small et al, 1995
Fluoxetine
Fluoxetine
Fluoxetine
Heiligenstein etal, 1995 Tollefson et al, 1995
Ackerman et al, 2000 Evans et al, 1997
500
Clomipramine
Petracca et al, 1996
20
261 OP
Nortriptyline Nortriptyline
Taylor et al, 1999 Taylor, 1999
20 NH
671 OP
671 OP
62 COM
671 OP
21 OP with AD
25
27 OP
50
Nortriptyline
Sample size
Miller et al, 1998
Dose in mg/d
Drug
Author
Table-10: Placebo controlled trials
DSMIIIR DSMIIIR
DSMlll-R
DSMIIIR
DSMIV
DSMIIIR
SADSL, RDC
SADSL, RDC
hi 87.9
68
67.7
80.4
>60
>60
72
Age range/ mean
6 week 8 week s 6 week s 6 week 8 week
16 week s 14 week s 6 week 6 week
Stud y duration 7 wks; 1 year
HAM-D, Cornell Depression, CGI, GDS,
HAM-D, GDS
HAM-D
HAM-D, CGI, GDR, PGI HAM-D
Health Status Survey HAM-D
Clinical evaluation. HAM-D HAM-D, MMSE
ECG
43% response; 28% remission by week 4; early responders do not always predict final response. Paroxetine similar to PLB for minor depression
Fluoxetine markedly superior to PLB, but no response predictors identified
The rate of subjects achieving response (HAM-D reduction of 450%) or remission (end point HAM-D) were in favour of fluoxetine and statistically significant Fluoxetine similar to PLB for moderateiy severely depressed patients. Only modest response in medically ill patients.
Fluoxetine » PLB
NT decreases REM time and %; increases REM density; REM measures revert with response. After NT withdrawal, patients severely depressed before treatment relapsed; less severely depressed were well maintained with interpersonal psychotherapy. Clomipramine better than placebo in achieving remission
Significant ECG changes reverted to baseline with PLB; cardiac disease patients had no worse changes than noncardiac patients
Outcome
50100 400
13 COM
Sertraline
Moclobemide
Methylphenidate Adjunct lithium
Schneider, 2003
Roth et al, 1996
Wallace et al, 1995 Hardy et al, 1997 12 OP
726 OP/IP
DSMIIIR
DSMIV
76.2
72.3
73.6
>60
89.2
31 NH with AD 747
77
22 OP with AD
8 days 2 years
8 week s 8 week s 6 week s
12 week s
HAM-D, MMSE, SCAG, CGI, BG-P HAM-D, MMSE MADRS, GDS
HAM-D, CGI-I, CGI-S.
HAM-D, CSDD, PDRS, MMSE CSDD, GS, CMAI
Significantly risk of relapse.
Rapid resolution of Sx in older medically ill patients.
The subjects who received sertraline exhibited greater and statistically significant improvement on the primary outcomes measure Overall Moclobemide had equal efficacy that of PLB; But moclobemide was better than PLB in demented patients.
Overall Sertraline similar to PLB; sertraline better than PLB for facial signs of depression.
Sertraline better than placebo; full remission in 25 %; partial remission in 50%
NT 10-30 vs NT 60-80
SERT 50-150 vs. NT 25-100 PAROX vs NT vs. PLB
Streim et al 2000
Bondareff el al 2000 Green et al 1999
DSM-IIIR DSM-IV
80 OP/IP
Diagnostic criteria DSM-IV
210
69 frail NH.
Table-11: Comparative trials of TCAs & SSRIs Author Drug in mg/day Sample size
75
67.8
Mean Age 79.5
2 weeks
' 2 weeks
Study duration 10 weeks
HAM-D
ADS, MMSE, POMS
HAM-D, CGI.GES
Rating scales
Sleep deprivation added to antidepressants produces rapid response
Regular dose slightly better than low dose; low dose much superior in coqnitively impaired subjects Equal efficacy
Outcome
AD- Alzheimer's Disease; CGI - Clinical Global Impression Scale; COM- comorbid medical illness; CSDD- Cornell Scale for Depression in Dementia; DSMIIIR- Diagnostic and Statistical Manual Revised -III edition; DSMIV- Diagnostic and Statistical Manual -IV edition; GAS- Global Assesment Scale; GDS- Geriatric Depression Scale; HAM-A- Hamilton Rating Scale for Anxiety; HAM-D- Hamilton Rating Scale for Depression; IP- inpatients; MADRSMontgomery-Asberg Depression Rating Scale; MMSE- Mini Mental State Exam;; NH- Nursing home patients; OP- outpatients; QOL- Quality of life; RDC- Research Diagnostic Criteria; SADS-L- Schedule for Affective Disorders and Schizophrenia—Lifetime
25100
Sertraline
Magai et al, 2000
12150
Sertraline
Lyketos et al, 2000
MMSE
Sertraline 25100 vs. NT 1080 PAROX, NT
Oslin, 2000
SERT 50 vs IMN150
CITA 20-40 vs. mianserin 30-60
CITA 20-40 vs. AMP 50-100
CITA 30-40 vs. NT 50-100
Fluvoxamine 100-200 vs. Dothiepin 100-
Forlenza et al 2000
Karlson et al2000
Kyle et al 1998
Narvarro, 2001
Rahman et al 1991
DSM-IV
(79) DSM-III
6 weeks
6 weeks
12 weeks
72.5
68.5
>64
70.6
12 weeks
6 weeks
12 weeks
8 weeks
8 weeks
83.1
m
DSM-IV
6 weeks
73.2 6-9 weeks
6 weeks
CM
58 OP with moderate to severe depression. 52 IP
DSM-III-R
DSM-IV
Clinical diagnosis
97 Frail NH
co o>
30 IP/OP with severe psychotic depression. 55 OP moderately depressed & demented 336 mild to moderate dementia and depression 365 PP
DSM-IIIR
20 dysthymic disorder OP
CO CO
NT 63.2 76.3 perphenazine 18.9-19.3, PLB
co Q r^
Mulsant et al 2001
> MADRS
HAM-D MMSE, UKU
MADRS, HAM-D, CGI
MADRS, CGI
CGI, MADRAS, MMSE
HAM-D, BPRS, side effects
HAM-D
MMSE-PSMS, HAMD
UKU SE Rating Scale HAM-D
EPS
3
71.6
X
Clinical Diagnosis
6 weeks
d < *
62 IP/OP
80 IP/OP
5
Pollock et al 2000
PAROX 10-30 vs. NT 25-100 PAROX 25 vs. NT 10 PAROX 20-30 vsNT NT, sertraline
Mulsant et al 1999 Mamo et al 2000 Pollock et al 1998 Nobler et al 2000
LU CO
Equal efficacy
43% response; 28% remission by week; early responders do not always predict final response. Cit= IMI for efficacy; IMI > Cit for side effects NT better than cit; remission of severe depression; NT better than cit for autonomic side effects
Equal efficacy; worse outcome in patients with dementia
Equal efficacy and tolerability
Serotonin transporter gene allele variations correlate with response to PAROX but not NT NT + perphen= NT+PBO for efficacy and tolerability
NT better than PAROX in terms of anticholinergic properties NT equal to sertraline; responders show reduced cerebral blood flow in frontal and anterior temporal regions NT better than SERT for efficacy; NT= SERT for tolerability.
Paroxetine equal to nortriptyline for efficacy and tolerability. Equal efficacy
236 OP
213 OP
19 in and outpatients DSM-III-R 75 OP
75.5
68
DSM-III-R
74
DSM-III-R
DSM-III-R
70
DSM-IIIR
12 weeks
2 years
12 weeks
6 weeks
Sertraline better than FLUOX in terms of efficacy, tolerability and cogn.'ive improvement TCA, MAOI>others, acute treatment and maintenance TCA=SSRI=MAOI=atypical, side effects Sert= fluox; sert better than fluox for cognitive improvement.
HAM-D, HAM-A, CGI, POMS, QLESQ, WAIS-R, DSST MADRS
HAM-D, HAM-A, CGI, MADRS, QLLES-Q, MMSE
Early antidepressant effects independent of REM suppression
Sleep study
DSM-III-R
74.5
6 weeks
MADRS, HAM-D
92 IP/OP
Mahapatra, 1997
Venafaxine 50-150 vs. Dothiepin 50150
Rating scales HAM-D, CGI DST
Table-12: Comparative trials using the newer classes of antide pressants Author Drug in mg/day Sample Diagnostic Mean Study size criteria Age duration Katona et al Reboxetme 4-6 vs 347 IP/OP DSM-III-R 74 8 weeks imipramine 50-100 1J9J Kin et al Moclobemide 400 71 95 DSM-III-R 7 weeks 1997 vs. NT 75 vs. PLB
DST positive patients had better NT response; DST negative patients better MOC response. Equal efficacy
Equal efficacy IMI better in dysthymia
Outcome
AD- Alzheimer's Disease; AMP- amitriptyline; BPRS- Brief Psychiatric Symptom rating Scale; CGI - Clinical Global Impression Scale; CITA- citalopram; COM- comorbid medical illness; CSDD- Cornell Scale for Depression in Dementia; DSMIIIR- Diagnostic and Statistical Manual Revised -III edition; DSMIV- Diagnostic and Statistical Manual -IV edition; DSST-Digit Symbol Substitution Test; DST-Dexamethasone Suppression Test; EPS- extra pyramidal symptoms; FLUOX- fluoxetine, GAS- Global Assesment Scale; GDS- Geriatric Depression Scale; HAM-A- Hamilton Rating Scale for Anxiety; HAM-D- Hamilton Rating Scale for Depression; IMN- imipramine; IP- inpatients; MADRS- Montgomery-Asberg Depression Rating Scale; MMSE- Mini Mental State Exam; NH- Nursing home patients; NT- nortriptyline; OP- outpatients; PAROX- paroxetine; POMS- Profile of Mood Slates; QOL- Quality of life, Q-LES-Q- Quality of Life Enjoyment and Satisfaction Questionnaire; ROC- Research Diagnostic Criteria; SADS-L- Schedule for Affective Disorders and Schizophrenia—Lifetime; SERT- sertraline; UKU -Udvalg for Kiiniske Undersogelser; WAIS- Wechsler Adult Intelligence Scale
Newhouse et al 2000
Sertraline 50100 vs FLUOX 20-40
Sertraline 50100 vs FLUOX 20-40 TCA vs SSRI vs. MAOI vs atypical
Finkel et al 1999
Mittmann et al 1999
Trimipramine vs. FLUOX
Wolf et al2001
2Q0
Nefazodone - 200400 vs imipramine 100 vs. PLB
Bupropion 100-300 vs. paroxetine 1040 Mirtazapine, trazadone & PLB
Mirtazapine Vs amitriptyline Mirtazapine Vs PAROX
Van Laar et al 1995
Weihs et al 2000
Schatzberg et al, 2002 Hoyberg et al, 1996
24 volunteers No. diagnosis 100 OP
177
109 IP/OP
DSM-IV
DSM-III.R
70
72
60+
6 weeks
6 weeks
7 days
8 weeks
7 weeks
HAM-D, HAM-A, CGI HAM-D
HAM-D, CGI, HAM-A Driving tests
comparable efficacy; mirtazapine group appeared to have a faster decrease in mean HAM-D (17 item) scores
Mirtazapine group had significantly lower HAM-D scores at the 6-week end point than did the placebo group. comparable efficacy
equal efficacy and tolerability
IMI impaired driving, high dose of nefaz also impaired driving; high doses of both impaired memory.
IMN>Buspar>PBO
NT>mocl>PBO remission rates
Equal efficacy
Venlafaxine superior to trazodone
CGI - Clinical Global Impression Scale; DSMIIIR- Diagnostic and Statistical Manual Revised -III edition; IP- inpatient; OP- outpatient; PLB- Placebo; PAROX- paroxetine; DSMIV- Diagnostic and Statistical Manual -IV edition; DST-Dexamethasone Suppression Test; HAM-A- Hamilton Rating Scale for Anxiety; HAM-D- Hamilton Rating Scale for Depression; IP- inpatients; MADRS- Montgomery-Asberg Depression Rating Scale; OP- outpatients; PAROX- paroxetine
Halikab et al, 1995
Imipramine vs. Buspirone vs PBO
Venlafaxine Vs Clomipramine Vs Trazadone Venlafaxine Vs Nortiptylme Moclobemide 400 vs. nortriptyline 75 vs. PLB
Schweizer et al 1998
Gasto et al, 2003 Nair et al 1995
Smeraldi et al, 1998
RCTs comparing side effects of TCAs (N=537) Vs SSRIs (N= 554)
Studies of poststroke depression in elderly inpatients published from January 1987 to August 1997
Treatments for depression in elderly medical Inpatients published from January 1987 to August 1997
Cole et al, 2001
Cole et al, 2000
! RCTs comparing at I least two active : antidepressant l drugs
i
| Inclusion ' Criteria
Wilson & Mottram, 2004
Mottram et al,2006
Author
• 55 or mean age •65
• 55 or mean age •65
>55
Age
of
Systematic literature search
Systematic literature search
Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register (CCDANCTR -Studies)
! Source data
Table-13: Meta-analysis of antidepressant trlalt
11
Studies irclude d 29
•
•
• •
No difference in efficacy between different classes of drugs TCAs less favorable than SSRIs in terms of numbers of patients withdrawn irrespective of reason (RR: 1.24, CI 1.04, 1.47) and number withdrawn due to side effects (RR: 1.30, CI 1.02, 1.64). Subgroup analyses demonstrated that TCA related antidepressants had similar withdrawal rates to SSRIs irrespective of reason of withdrawal (RR: 1.49, CI 0.74, 2 98) or withdrawal due to side effects (RH: 1.07, CI 0.43, 2.70). The qualitative analysis of side effects showed a small increased profile of gastro-mtestinal and neuropsychiatnc side effects associated with classical TCAs TCAs had an increased withdrawal rate (RR: 0.24, CI 1.04, 1.47). A similar rate of side effects was fou hen comparing classical TCAs (451 patients) (amitriptyline, clomipramine, doxepin and dothiepin) with SSRIs (466 patients) (RR 1.30 CI: 1.02, 1.64). Increased prevalence of side effects including dry mouth, drowsiness, dizziness and lethargy in the TCA group No differences were found in the side effects when comparing TCA related drugs (mianserin and trazadone) with SSRIs (RR 1.07 CI 0.43, 2.70). The limited evidence suggests contraindications to treatment of 8 3 % of a group to receive a heterocyclic antidepressant compared with 1 1 % of a group to receive a (SSRI); Rates of discontinuation and study completion are similar for heterocyclics, SSRIs and psychostimulants All of the treatments appear to be at least modestly effective in the short term
• The limited evidence suggests contraindications to treatment in 3 8 % to 8 7 % of subjects who received a heterocyclic antidepressant compared to 4 % of subjects who received the SSRI • Rates of discontinuation and study completion were similar for heterocyclics, the SSRIs, and psychostimulants. • All of the treatments (including social support/ psycho-therapy) appeared to be at least modestly effective in the short term.
•
•
•
•
•
• •
Results/Conclusions
Amrein et al, 1997
Mittmann et al, 1997
McCuske r et al.1998
Gerson et al, 1999
Treatment response and tolerability of pharmacological and psychological treatments for depression published between January 1974 and February 1998 Prospective control trials of acute-phase treatment of mifd to moderate depression with pharmacological and psychological treatments in older ambulatory patients Double-blind RCTs evaluating 1 antidepressants in moderate/ severe depression of atleast four weeks duration Comparative trials of moclobamide, TCAs and SSRIs •60
•60
•55
•55
Systematic literature search
37
• Moclobemide is an effective antidepressant in elderly depressed patients with a response rate of 50% to 55%. • Moclobemide is more effective than placebo but is similar to TCAs and SSRIs. • The tolerability of moclobemide is rated as "very good" or "good" in almost 90% of patients, which was better than the tolerability of TCAs and similar to that of SSRIs. • Patients without any adverse events were more frequently found in the moclobemide group than in those treated with TCAs (P < 0.01) or SSRIs (P
others, acute treatment and maintenance TCA=SSRI=MAOI=atypical, side effects
Combination treatment was superior to placebo plus clinical-management sessions in preventing recurrences in older subjects who have had multiple episodes. Drugs combined with IPT better; higher recurrence in 70+ compared with younger patients
Maintenance treatment with full-dose antidepressants resulted in 70% cumulative probability of surviving without relapse or recurrence Maintenance treatment with full-dose antidepressants resulted in 74% cumulative probability of surviving without relapse or recurrence. Anxious patients had a higher relapse rate over a 2- year follow-up period.
Outcome
0.01). • Adverse events of the anticholinergic type were more frequent with TCAs than with moclobemide (P < 0.001), and nausea was found 3 times more frequently with SSRIs than with moclobemide (P < 0.01). RCT- randomized control trials: TCA-tricyclic antidepressants; RR- relative risk; CI- confidence interval; SSRI- selective serotonin reuptake inhibitors;
PAROX vs. NT CITA Vs PLB
Sertraline Vs PLB
PAROX+ IPT Vs PAROX + CM Vs IPT +CM Vs PLB + CM
Bump et al 2001 Klysner et al, 2002
Wilson et al, 2003
Reynolds et al, 2006
113
60
116 OP
depression 28 delusional depression
DSMlll-R
SADSLROC
SCID-P
>70
77.1
>65
72.5
71.8
2 years
2 years
48- week
24 weeks
26 weeks
HRDS
HAM-D Barnes Akathisia; Simpson Angus; AIMS HAM-D, MMSE, GAS, MATTIS MADRS
32% of citalopram-treated patients had relapsed compared with 67% of the placebo group (P > pharmacotherapy for efficacy; no long term side effects. Rao & Lyketosos 2000 31 MADRS, MMSE ECT effective treatment for depression with dementia; improvements in mood and cognition; multiple treatments necessary; 1/2 of patients developed delirium Stoudemire et al 1998 39 71 HAM-D 90% recovery rate; 29% relapse rate despite LIFE maintenance antidepressants. Tew et al 1999 60-74, 75+ 268 HAM-D Best response in 60-74 followed by 75+; well tolerated, even in oldest patients. Tomac et al 1997 34 >85 HAM-D, HAM-A, Very elderly with concurrent medical problems tolerated ECT well. MMSE, BPRS Serra et al, 2006 39 During maintenance combined ECT plus nortriptyline was better than nortriptyline alone in relapse prevention Fraser and Glass. 1980 33 73 97 % of the subjects recovered or improved Casey and Davis, 1996 18' 79.5 86,3 % ot the subjects recovered or improved Gaspar & Samarasmghe, 1982 33 73.9 78.8 % of the subjects recovered or improved Karhnsky & Shuiman. 1984 33 73.2 78.8 % ot the subjects recovered or improved Godber & ai 1987 163 76 74 % ot the subjects recovered or improved Benbow, 1987 122 73 80 % ot the subjects recovered or improved Rubin el ai. 1991 46 75.9 78 % of the subjects recovered or improved Wilkinson et al. 1993 43 73.9 73 % of the subjects recovered or improved BPRS- Brief Psychiatric Symptom rating Scale; HAM-A- Hamilton Rating Scale for Anxiety; HAM-D- Hamilton Rating Scale for Depression; UFELongitudinal Interval Follow up evaluation; MADRS- Montgomery-Asberg Depression Rating Scale; MMSE- Mini Mental State Exam
Flint & Rifat 1998a
Table-18: Treatment outcome of psychotheraples in old-age depression diagnosis Author No of age Type of Control Outcome subjects psychotherapy group MDD 67Immediate Vs CBT was efficacious in immediate and delayed Fry , 1984 75 80 Late CBT treatment subjects MDD Thompson et al, 1987 67.1 CT, BT, BDT Wait list All three therapies were efficacious 91 MDD 64CBT CBT efficacious in reducing depression Campbell, 1992 103 Notrt 82 MDD Gallagher-Thompson & 62 CBT, BDT NA BDT better for "new" caregivers, CBT better for 66 Steffen ,1994 "seasoned" caregivers MDD Arean et al, 1993 55+ PST, RT Wait list PST better than RT 75 MDD Primary care Nurse CT intervention effective Blanchard et al, 1995 78.2 CT nurse 96 intervention control Unutzer et al, 2002 MDD >60 IMPACT Usual care IMPACT significantly more effective than usual care 1801 Thompson et al, 2001 MDD DIMN, CBT, 102 >60 NA All kind of treatments effective, combined therapy DIMN+CBT better, most effective for most severe depression Gallagher -Thompson et 91 >60 MDD CT, BT, BDT Wait list All therapies were efficacious, no difference in gains al, 1987 by psycho-therapies in maintenance treatment Reynolds etal,1999 67 Recurrent NT, NT+IFT, 187 Pili-PLB NT plus IPT most efficacious MDD IPT+PLB Fry, 1983 MDD Structured RT 162 65Notrt Both treatments efficacious 82 Unstructured RT Structured > Unstructured Blanchard et al, 1999 78.2 MDD No treatment 64 Comprehensive Psychotherapeutic interventions efficacious for intervention with Maintenance psychotherapy/m edication Area'n& Miranda, 1996 Medically ill Individual vs 182 >60 NA Psychotheraples effective in medically ill elderly in OP group CBT follow up Mossey etal,1996 Minor Dep >60 76 IPC Usual care IPC more efficacious at 6-month follow-up Minor dep/ Williams et al, 2000 71 Paroxetine, PST Pill-placebo 415 Paroxetine moderately efficacious, PST more dysthymia variable in efficacy Ciechanowski et al, 2004 138 Minor dep/ >60 PEARLS Usual care PEARLS program significantly more effective than dysthymia usual care Wang , 2005 94 Dep. Sx 65 RT NoTrt RT more effective MDD- Major depressive disorder; CBT- cognitive behavior therapy; BT- behaviour therapy; CT- cognitive therapy; BDT- brief dynamic therapy; PSTproblem solving techniques; IMPACT- ; DIMN- desipramine; NT- nortriptyline; PLB- Placebo; RT- Reminiscence therapy; IPC- Interpersonal counselling; PEARLS-
Table-22: Antidepressants, with their initial geriatric dose, maximum dose and common side effects Antidepressant
Usual dose Starting dose in mg/day range Selective serotonin reuptake inhibitors (SSRI) Fluoxetine 5 - 1 0 Paroxetine 5 - 1 0 Fluvoxamine 25-50 Sertraline 12.5-25 Citalopram 10-20 Escitalopram 5 - 1 0 Tricyclic tertiary amines (TCAs) Amitriptyiine Doxepin Imipramine Clomipramine Tricyclic Secondary
10-25 10-25 10-25 10-25 Amines
Desipramine 10-25 Nortriptyline 10-25 Protriptyline 5-10 Tetracyclic Maprotiline | 25 Unicyclic Bupropion 75- 100
Common side effects
5-40 5-40 25-200 12.5-150 10-20 5-20
Sexual dysfunction, Gl distress, weight loss/gain, anxiety, insomnia
25-150 25-75 50-150 50-150
Sexual dysfunction, anticholinergic effects, drowsiness, orthostasis, conduction abnormalities, mild Gl distress, weight gain Aviod amitriptyiine and doxepin
75-150 50-150 15-20
Relatively safer TCAs in elderly
50-75 Maximum geriatric dose - not established conduction abnormalities, mild Gl distress, high risk of seizure after 450 mg/day
75- 300
Norepinephrine Serotonin reuptake 1nhibitors (NSRI ) Venlafaxine 12.5-37.5 50-225 Mild anticholinergics effects, drowsiness, Duloxetine 20 40-60 conduction abnormalities, Gl distress Norepinephrine Serotonin Reuptake Enhance (NSR E) Tianeptine \ Noradrenaline and Specific Serotoni i Antidepressa nts (NaSSA) Mirtazapine 7.5 15-30 Mild anticholinergic effects, drowsiness, orthostasis, conduction abnormalities, Gl distress, weight gain Atypical antidepressants/Serotonin 1Modulators Trazadone Netazodone
25 100
Trazadone should be avoided Mild anticholinergic effects, drowsiness, orthostasis, conduction abnormalities, Gl distress, weight gain, severe hepatotoxicity Reversible Selectiv e Mono Amine 0>cidase Inhibitor s (RIMA) 75- 150 200-400
Moclobemide ! Mono Amine Oxida se Inhibitors (MA 01) Phenelzine j | 45-90
1 | Orthostatic hypotension
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Conclusion about use of antidepressants in elderly: The above reviewed data has lot of limitations. All the above trials are efficacy trials, not effectiveness trials.That is, they examine antidepressant response in a narrowly defined patient population, typically excluding subjects for many reasons, such as comorbid psychiatric illnesses including psychosis, addictions or personality disorders, subjects with significant medical comorbidity, and subjects with poor treatment response histories. Thus the results of these studies do not necessarily generalize to 'typical' clinical populations where these comorbidities are commonplace. Hence, large trials of commonly used antidepressants utilizing few exclusion criteria are desperately needed. More research is needed into more efficacious antidepressant agents, reasons why individuals do not respond to current antidepressants, and better, evidence-based strategies for treating these individuals. Based on published reports, following conclusions can be drawn about the acute phase treatment: 1. There is lot of variation between the methodoiogies used in various studies 2. Most of the studies have been done in major depression 3. There are very few studies for minor depression, dysthymia, psychotic depression, depression in medically ill. 4. Antidepressants are better than placebo 5. There is no difference in efficacy in acute treatment between different classes of drugs 6. Antidepressants are well tolerated by elderly subjects 7. Antidepressants are at least modestly effective in the short term treatment of post-stroke depression and depression in medically ill subjects 8. Although TCAs have more side effects than SSRIs, but the difference is very small and not significant statistically 9. There are very few trials with newer antidepressants including escitalopram 10. Drug trials have failed to recognize any predictor of response to treatment Substitution, Augmentation/combinations in nonresponders and poor responders The goal of the acute phase of treatment is to achieve complete remission of depressive symptoms. However this is not always possible. About 30% of elderly patients do not respond to an initial adequate trial of antidepressant medication and require additional or alternative treatment137. Patients, who respond partially to treatment, or not at all, can be managed by either substitution or augmentation. Substitution, involves changing from one treatment to another. There are virtually no data on antidepressant substitution in refractory depression that occurs in late life and authors have tried to extrapolate the findings of patients of mixed ages to old age. As a general rule, switching to another antidepressant within the same class, for example from one TCA to another, is less effective than switching to one from another class. But there are exceptions to the above rule138. Some open and uncontrolled studies have reported response rates of 50% and 63% among younger adult outpatients who failed to respond to one SSRI and were then treated with another139140. These findings must be considered preliminary, but they suggest that it may be reasonable to consider a second SSRI trial before switching to another class of antidepressant. When switching antidepressants in elderly patients, it is advisable to withdraw the first agent gradually (e.g., over 1-2 weeks) before introducing the new drug. However, even with this gradual crossover the patient needs to be carefully monitored for the possible effects of drug-drug interaction. A drug-free period of 2 weeks is required when switching (89)
from a first-generation MAOI to another antidepressant and 6 weeks when switching from fluoxetine to a first-generation MAOI. Data suggest that venlafaxine may be particularly useful in patients who have not responded to other antidepressants. A review of 3 double-blind comparisons141'43 and 4 open-label studies144147 involving the use of venlafaxine in older patients concluded that venlafaxine was safe and effective in elderly patients with major depression148. On the basis of the above evidence, an expert consensus panel on the treatment of depression in the elderly, proposed venlafaxine as both an alternative first-line antidepressant for severe depression and an agent for SSRI nonresponders. However, studies also suggest that venlafaxine is not safe in frail elderly subjects. Augmentation refers to the addition of another medication to the antidepressant. The adjunctive agent may be a second antidepressant (e.g., adding aTCA to an SSRI) or a medication that is not primarily an antidepressant (e.g., lithium, triiodothyronine, methylphenidate, buspirone or valproate). The advantage of augmentation is that it does not require discontinuation of the original antidepressant, and therefore patients who partially responded to treatment are not put at risk of returning to their baseline severity of depression. Also, response may be faster with augmentation than with a new trial of antidepressant medication.The disadvantage of augmentation, especially in elderly people, is that the combination of medications increases the risk of side effects and of drug-drug interactions. There are very few controlled trials of augmentation in elderly people, and therefore the effectiveness of this approach in treating geriatric depression have not yet been established 149. Lithium augmentation: In a retrospective study Finch & Katona150 used lithium to augment the treatment of depression in 9 subjects of either unipolar or bipolar depression who failed to respond to tricyclic antidepressants, of whom four had also failed to respond to ECT. Lithium augmentation was successful in 6/9 subjects. Out of the 3 lithium failures, 2 were treated with tranylcypromine to good effect. At follow-up (median six months, range 3-20 months) 7/9 subjects in the lithium-treated group were well. This was similar to the follow-up status in tricyclic responders and significantly better than outcome in the other tricyclic non-responders. Antidepressants combinations: Whyte et al151 augmented the treatment of 53 elderly subjects with major depressive disorder according to DSM-IV criteria who failed to respond to paroxetine plus interpersonal psychotherapy with either bupropion sustained release, nortriptyline, or lithium. Subjects who did not respond to the above 3 agents entered a subsequent trial of venlafaxine XR. Twelve subjects subsequently received venlafaxine XR monotherapy. Response to treatment was defined as a 17-item Hamilton Rating Scale for Depression score of < 10 for 3 weeks. Sixty percent of subjects (N = 32) responded to some form of combination/augmentation, with 45% (24/53), 31% (5/ 16), and 43% (3/7) responding to bupropion sustained release, nortriptyline, or lithium, respectively. The mean time to response after starting the first augmentation/ combination trial was 6.0 (SD = 5.8) weeks. Forty-two percent (N = 5) of the venlafaxine XR-treated subjects responded with the mean time to response of 6.4 (SE = 0.9) weeks. Adverse effects leading to treatment discontinuation and falls were more common in the augmentation subjects than in the venlafaxine XR subjects. Citalopram & Methylphenidate: Methylphenidate has been evaluated as a combination agent by one group of researchers in 3 trials: 2 open label and a double blind trial. In an open label trial Lavretsky & Kumar152 studied 10 elderly depressed patients (mean age=79.8 years) with combination of citalopram with methylphenidate and found that 8 of the 10. patients demonstrated clinically significant
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improvement by week 8. Four of the 7 patients with combination initiated during the first week of treatment with citalopram met the criteria for rapid response at week 2.Lavretsky et al' 53 evaluated the potential of methylphenidate to accelerate antidepressant response to citalopram and the safety and tolerability of the combined treatment in 11 elderly outpatients aged 70 years and older diagnosed with DSM-IV major depressive disorder in a 10-week, open-label trial. Methylphenidate was tapered and discontinued during weeks 9 and 10. Response was defined as a Hamilton Rating Scale for Depression (HAM-D) score of less than 10. The daily dose of citalopram ranged between 20 and 40 mg, and the daily dose of methylphenidate ranged between 5 and 20 mg. Out of the 9 patients who completed the study, 6 met criteria for accelerated response (HAM-D score < 10 and Clinica1 Global Impressions-Improvement scale score of 1 or 2 by treatment day 14), and 2 more patients responded by week 3. One patient was a nonresponder. The observed side effects were mild to moderate in severity and included sedation, nausea, anxiety, polyuria, dry mouth, and hypersalivation. In doubleblind, placebo-controlled trial Lavretsky et al154 evaluated the potential of methylphenidate to accelerate and enhance antidepressant response to citalopram in elderly depressed patients. Sixteen outpatients with major depression were treated for 10 weeks either citalopram and placebo or citalopram and methylphenidate. Response was defined as a score on the Hamilton Depression Rating Scale (24item) of less than 10. An accelerated response was observed by week 3 in five subjects receiving citalopram and methylphenidate and in none of those receiving citalopram and placebo. Subjects receiving citalopram and methylphenidate showed a significant improvement in depressive symptoms compared with those on citalopram and placebo. ModafinikThere are case reports of successful use of modafinil as an augmenting agent to fluoxetine in elderly man with history of myocardial infarction155. In another case report Schillerstrom & Seaman156 successfully used combination therapy of modafinil and mirtazapine in a patient with multiple myeloma withfailure-to-thrive. Dexamethasone: It have also all been tried in case reports and found to be useful157.Maintenance treatment of depression in elderly As in young adults, depression has a strong tendency to recur in elderly persons, with rates of recurrence of 50 to 90 percent over a period of two to three years; hence, the goal of treatment should be not only recovery from current episode, but also the prevention of recurrence236. However compared to young adults, there are few controlled studies on the efficacy of maintenance antidepressant medication or depression-specific psychotherapy in elderly patients. The noncontrolled & controlled studies done for maintenance treatment of elderly depression are shown in table-14. As is evident from the table-14, there are only 2 controlled trials each which have evaluated 'he use of paroxetine and nortriptyline and only 1 trial each of sertraline and citalopram. The sertraline trial did not show any benefit of sertraline over placebo for maintenance treatment. However, in the citalopram trials it was reported that there was lower risk of relapse with citalopram in comparison to placebo and additionally the time taken to relapse was also longer. The trials have also shown that combination of antidepressant and psychotherapy to be superior to either given alone. In some studies it has been found that presence of anxiety during the acute phase, presence of residual symptoms during continuation phase and increasing age predicted relapse. In another study presence of cognitive impairment did not predict relapse or recurrence of major depression in late life.
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Figure -1: Treatment algorithm of minor depression and mild to moderate Depression in elderly
Minor Depression Mild to moderate Depression
I
Evaluate for the type and severity of depression Evaluate for past history of depression Evaluate for past history of treatment and response Evaluate for family history of depression Evaluate for physical and psychiatric comorbidity Evaluate for concomitant drugs which patient is receiving Evaluate for the presence of psychosocial stressors Evaluate the cognitive functions Patient's preference No past history of depression Minor or mild depression Presence of psychosocial stressors Past history of good response
Patient's preference Past and family history of good response Low risk of drug interactions Moderate depression
No cognitive deficits
Receiving other medications and high risk of drug interactions
Pharmacotherapy
Psychotherapy
Remission
No response
Partial response
I
Change to antidepressant
Optimize the treatment increase the frequency of psychotherapy^ Increase the dose of antidepressants to maximum tolerable dose
Remission
No response
Change antidepressant or Switch to psychotherapy
I
Change/Combination • If receiving psychotherapy - add antidepressants • If receiving antidepressants - add psychotherapy or change the antidepressant
I
Augmentation/Combination • If receiving antidepressants - add second antidepressants/ augmenting agent taking into consideration the issue of tolerability and side effects 23
(92)
Figure -2: Treatment algorithm of Severe Depression in elderly
Severe Depression
I
Evaluate for past history of depression Evaluate for past history of treatment and response Evaluate for family history of depression Evaluate for physical comorbidity Evaluate for concomitant drugs which patient is receiving Evaluate for the presence of psychosocial stressors Evaluate the cognitive functions Evaluate for suicidality, oral intake
Patient's preference Past history of good response Receiving other medications and high risk of drug interactions Suicidal Poor oral intake Catatonic symptoms
Patient's preference Past and family history of good response Low risk of drug interactions
Pharmacotherapy ECT+ Pharmacotherapy (ECT for treatment of acute disturbance and antidepressants for the continuation phase)
I
Partial response
No response
Optimize the treatment • Increase the dose of antidepressants to maximum tolerable dose
T
No further response
> Switch to an antidepressant from same or different pharmacological class or dual acting agent > AddECT > Add second antidepressants/ augmenting agent taking into consideration the issue of tolerability and side effects
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Figure -3: Treatment algorithm for continuation phase treatment of depression in elderly
Continuation Phase treatment
Treated with antidepressants during the acute phase
Continue antidepressants at the same dose for 1 year after achieving remission
Treated with psychotherapy during the acute phase
Treated with combination of psychotherapy and antidepressants during the acute phase
Continue psychotherapy at the same or decreased frequency for 1 year after achieving remission
I
Continue with antidepressants at the same dose and psychotherapy at the same or decreased frequency for 1 year after achieving remission
Treated with combination of antidepressants and ECT/anti psychotics during the acute phase
I
Continue with antidepressants and antipsychotic at the same dose and for 1 year after achieving remission
Monitor for relapse of symptoms
No past H/O depression
Past H/O depression
Discontinue treatment
Maintenance Treatment (94)
Figure -4: Treatment algorithm for maintenance phase of depression in elderly
Maintenance Phase treatment (H/O of > 2 episodes)
T
T • Treated with antidepressants during the acute and continuation phase » Treated with combination of antidepressants and ECT/ antipsychotics during the acute and continuation phase
Treated with psychotherapy during the acute and continuation phase
• Treated with antidepressants and psychotherapy during the acute and continuation phase
I
• Continue with same treatment preferably for life long • Monitor symptoms and treatment tolerability
Figure -5: Treatment algorithm for discontinuation of treatment in elderly
Discontinuation of treatment
' ' • Discontinue the antidepressants over few weeks to few months • Monitor for discontinuation syndromes • Terminate the psychotherapy as per needs of the patients
i
r
• Monitor for relapse • Reinstitute the previous therapy as soon as possible in case of relapse
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Figure -6: Treatment algorithm for inadequate response to flrst antidepressant therapy in elderly
Inadequate response to first antidepressant
I
Reevaluate the diagnosis Exclude comorbid medical and psychiatric disorder Review dose
I
Optimise the dose of first antidepressant Patient apparently resistant to optimal dose
Continue optimum dose for 4 weeks No response
Partial response Reevaluate dose and continue optimum dose for further 2 weeks Still partial response Switch to an antidepressant from same or different pharmacological class or dual acting agent
No further improvement
• •
T
Still partial response
Add ECT Combine with antidepressant from different pharmacological class or augment with a non-antidepressant taking into consideration the issue of tolerability and side effects
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ECT in old age depression Pippard & Ellam246 carried out a National survey of ECT usage in Britain and found that 37% of ECT courses were given to people aged over 60 years of age. By 1999. this figure increased and people = 65 years of age accounted for 44% of the women treated and 33% of the men247. Similar higher use and increasing trend of use of ECT has also been reported from USA248249. Kramer249 reported that compared to 1.12 per 10,000 adult population receiving ECT, the rate for elderly population was 3.86 per 10,000 population. It is now increasingly been shown that older people are no less likely to respond to ECT than younger people. But some important issues must be remembered while using ECT in elderly subjects. The elderly subjects, particularly men, tend to have an increased likelihood of a high seizure threshold and this may lead to difficulty in eliciting effective seizures250252.The choice of anaesthetic agent should also take into account the higher seizure threshold and other age-related factors. The seizureshortening effect of propofol and its possible effect on seizure threshold will need to be taken into account in choosing an anaesthetic drug. Some of the factors influencing the seizure threshold have been shown in table-15 and some basis facts about use of ECT are listed in table-16. It has also been suggested that older people, especially those who have pre-existing cognitive deficits when treated with ECT are more vulnerable to the development of cognitive side-effects during treatment and at risk of the cognitive side-effects lasting longer253. To counteract this problem some of the recent studies have reported that in elderly depressive subjects, high-dose right unilateral ECT is as effective as BL ECT but it produces less adverse effects and less cognitive impairment254. There is also an impressive positive association between patient age and the degree of clinical response after ECT255 257. However this positive association may be just a reflection of some of the clinical factors that influence the ECT referral and outcome. As many elderly subjects have medication intolerance, medical complications, psychotic depression compared to younger subjects they are referred for ECT with a shorter duration of current episode and a lower rate of medication resistance, both of which have shown to be consistent predictors of positive ECT outcome165. ECT and Concurrent Physical illness: Over the years it has increasingly become clear that there is no absolute contraindication to ECT. The potential risk and benefit should be weighed on case to case basis and where ever warranted the medical treatment should be optimized before ECT. The illnesses affecting cardiovascular system have received most attention in ECT research in old age. Studies have reported that there is increased risk of complications in people who are on more number of medications, especially those who are on more number of cardiovascular medications259. However, recent studies have shown that cardiovascular complications arising during ECT are transient and don't prevent successful completion of treatment course260. Efficacy of ECT in old age Studies which have reported the efficacy of ECT are shown in table-17. Overall, from these studies it can be concluded that ECT is efficacious and well tolerated even in patients of old age depression even by subject more than 80 years of age. Some studies have also reported it to be more efficacious than antidepressants. The side effects reported include an increased risk of falls, post-ECT delirium or dementia. Various retrospective studies indicate that patient's age and medical status are predictors of the development of persistent confusion during the ECT course281282. Older patients and those with compromised medical status are at highest risk for prolonged confusion.
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Continuation/Maintenance ECT: In one study, during the 2 years of maintenance treatment in elderly psychotic unipolar depressed patients who were treated with ECT during the acute phase, relapse/recurrence rates were significantly higher in the nortriptyline subgroup than in the combined ECT plus nortriptyline subgroup but both the treatments were equally tolerable283. Psychotherapies in elderly depressed subjects Various psychotherapies have been used for the treatment of depression in elderly. Out of the various psychotherapeutic models cognitive behavior therapy (CBT), interpersonal psychotherapy (IPT) and brief dynamic therapy (BDT) have been commonly used in elderly. CBT is based on the theoretical assumption that human behavior is learned and it involves strategies to change peoples perception of their psychosocial environment (cognitive restructuring), skill building (problem-solving, communication skills), and mood regulation skills (behavioral activation). Although both problem-solving therapy and CBT invt /e a combination of skill building and cognitive restructuring; Problem solving technique (PST) is focusud explicitly on improving problem resolution skills, whereas CBT focuses on affect and cognitive regulation skills. Interpersonal psychotherapy consists of elements of psychodynamic-oriented therapies (exploration, clarification of affect) and CBT (behavior change techniques, reality testing of perceptions) that are used to address four areas of conflict: unresolved grief, role transitions, interpersonal role disputes, and interpersonal deficits. According to brief psychodynamic perspective, depression occurs due to unresolved, unconscious conflicts with their roots in early childhood. The goal of BDT is to make the subject understand and cope better with these feelings. It focuses on reflections of past experiences, clarification of affect, the therapeutic relationship, and the confrontation of maladaptive interpersonal patterns, wishes or conflicts. Life review and reminiscence therapies are usually based on Eriksonian developmental theory, and were specifically developed for older ackilts. It is proposed to counteract learned helplessness by promoting an individual's feeling of control over past and present life events. Efficacy of Psychotherapies in elderly depressed subjects The efficacy of psychotherapy for the treatment of late life depression has been a topic of debate. In 1991, the National Institute of Health consensus statement on the treatment of late life depression ranked psychotherapy as third in a line of treatment options, (antidepressant medication first and electroconvulsive therapy second), indicating that there was insufficient evidence to recommend psychotherapy as a first-line treatment for depression in older adults284. Since that time, numerous articles have been written reviewing the psychotherapy research in older adults, and 4 meta-analyses of existing trials have been conducted. In addition, several randomized clinical trials meeting guidelines of recommendations for evidence based interventions have evaluated the efficacy of psychotherapy as a treatment for late life depression. Most of these studies have focused on the evaluation of cognitive-behavioral therapy (CBT) and interpersonal psychotharapy (IPT), brief dynamic therapy (BDT) and, combination of various types of psycho-therapies with antidepressant medications. Here we will review the available literature for the efficacy of psychotherapy (see table-18) and its combination with medication in the treatment of late life depression. Behavioral and Cognitive-Behavioral Therapies: CBT have received the most research attention of any psychotherapy for late life depression and
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research suggests that CBT is a viable therapeutic option for older subjects suffering from major depression and to a lesser degree for dysthymia and minor depression. Although several types of interventions fall under this category of psychotherapy, CBT, and problem-solving therapy (PST) have been evaluated in older adults (although BT has been used primarily as a comparison condition with CBT). Eleven well designed randomized clinical trials or follow up studies meeting the criteria for evidence based interventions have been published by various researchers. These studies have taken elderly subjects with major depression, minor depression and dysthymia. Three of these studies have used usual care as the comparison, 2 studies each have used wait list or no treatment as controls and in one study placebo treatment was used. Major depression: Six RCT have compared CBT with usual care or wait -list controls and all have reported CBT to be superior to usual care for depression, wait list control, pill-placebo, and no treatment. Some studies have also claimed that the treatment gains persist over long periods of time. Trials which have compared CBT with other psychological interventions have shown that CBT is either equally efficacious (to BT and brief dynamic therapy) or more efficacious (Problem solving better than reminiscence therapy). Only 1 study has compared the efficacy of CBT with antidepressants and it has shown that CBT and CBT plus desipramine were more efficacious than desipramine alone. Dysthymia and minor depression: Only 2 studies have evaluated the efficacy of CBT on dysthymia or minor depression. Williams et al171 compared problem solving with paroxetine and pill-placebo for the treatment of dysthymia and minor depression and reported that although both active interventions were effective in reducing the depression and improving functioning, paroxetine was better than problem solving. Problem solving was found to have slower onset of treatment effect and was influenced by the degree of therapist training. In another study modified problem solving therapy was shown to be more effective than usual care in reducing the depressive symptoms, improving quality of life and promoting remission. Interpersonal therapy There are few studies which have evaluated the efficacy of IPT alone in older subjects. In one study IPT plus pill-placebo was found to be better than pill-placebo alone in preventing the recurrence of major depression. In the same study it was also found that combined treatment of IPT and antidepressants produce best relapse prevention during the maintenance phase, whereas IPT plus placebo produce the worst rates. There it can be concluded that IPT may be most effective as a maintenance treatment for severely depressed older adults when administered along with antidepressants. Only one study has evaluated the efficacy of IPT against usual care for minor depression after 6 months of treatment and reported that IPT was superior to usual care in reducing the symptoms. There are no studies which have evaluated the use of IPT in geriatric dysthymic subjects. Brief dynamic therapy Brief psychodynamic therapy has mostly been used as a comparative arm for CBT. It has been evaluated only in major depression and has been found to be effective. It has also been evaluated for maintenance treatment for depression for 1 to 2 years period and has been found to be equally efficacious to other treatments.
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Reminiscence therapy (RT) Research on RT suggests that it is a potentially useful intervention for the treatment of late-life depression. Both structured and unstructured life review therapies have been found to be effective when compared with no treatment control conditions in ambulatory community-based adults with major depression. In one study it has been found to be less effective than problem solving, in reducing depressive symptoms. Psychotherapy combined with antidepressants Preliminary data suggests that combined treatments are better than monotherapies in the treatment of late-life depression. Combination of antidepressants and IPT has been found to be most efficacious in treating major depression in ambuiatory older adults who have chronic or recurrent depression. In another study combination of CBT and desipramine was found to be superior to desipramine alone, but there was no difference between CBT ale and combination group. From the above it can be concluded that CBT, RT, BDT and the combination of antidepressants and IPT are efficacious in the acute phase of major depression in ambulatory geriatric subjects.There is also evidence for the combination of medications and IPT as a means of preventing relapse and recurrence of major depression. However more research is needed with well designed controlled trials with large sample sizes, especially for subjects with minor depression, dysthymia, in those with mild cognitive deficits, medically ill frail subjects. More research is also required to determine the long term outcomes, impact on functional outcomes and on medical and psychiatric comorbidity. Meta-analysis of psychotherapies 4 meta-analyses have also shown that psychotherapies are effective in elderly depressed subjects. Scogin et al299 examined the efficacy of 17 studies of psychosocial treatments in which a control groups included those receiving another psychosocial treatment or no treatment, delayed treatment, or placebo treatment was available. They concluded that treatments were reliably more effective than no treatment, when evaluated by self-rated and clinician-rated measures of depression. McCusker et al137 carried out a meta-analysis of prospective control trials of acute-phase treatment of mild to moderate depression with pharmacological and psychological treatments in older ambulatory patients and found that rational psychological treatments performed significantly better than no treatment (mean posttreatment Hamilton Depression Rating Scale difference, -7.25; 95% confidence interval, -10.10 to -4.40) but not significantly better than that for controls who received similar attention. Gerson et al232 in their meta-analysis of studies reporting treatment response and tolerability of pharmacological and psychological treatments for depression published between January 1974 and February 1998, concluded that in relation to the nonpharmacological treatment data indicate that cognitive-behavioral, behavioral, and psychodynamic therapies are significantly better than placebo and the response rates to nondrug therapies was not significantly different from those observed with tricyclic antidepressants or selective serotonin-reuptake inhibitors, but direct comparison data are insufficient for firm conclusions to be drawn about comparative efficacy. In another meta-analysis Bohlmeijer et al300 analyzed the effectiveness of reminiscence and life review on depressive symptomatology in elderly people by including 20 controlled outcome studies. They found an overall effect size of 0.84 (95% Confidence Intervals (Cl)=0.31 -1.37), indicating a statistically and clinically significant effect of reminiscence and life review on depressive symptomatology in elderly people. This effect was (100)
comparable to the effects found for pharmacotherapy and psychological treatments. The effect was larger in subjects with elevated depressive symptomatology (d=1.23) as compared to other subjects (cMD.37). Other treatment strategies used in old age depression Besides antidepressants, many other agents have been tried in old age depression, especially in those with associated medical illness.These include estrogen, testosterone and transcranial magnetic stimulation. Estrogen:Two studies have evaluated the use of estrogen in depression. In one study conducted in women who underwent hysterectomies showed a decrease in depressed mood after 6 months of estrogen treatment. However, the sample size (n = 12) was very small and they were relatively young301. However a randomized control trial which evaluated the effect of estrogen in post menopausal women did not report the same effect using 0.1 mg/day estradiol skin patches, and the response was similar to placebo after 8 weeks307. Testosterone:Testosterone was evaluated in 1 small study (n = 16) for 8 weeks and it was found that testosterone quickly reduced depression in older men, but there was no comparison arm in the study. The improvement was similar whether the men received 100mg or 200mg testosterone cypionate per week303. Transcranial magnetic stimulation: Transcranial magnetic stimulation (TMS) involves stimulating specific regions of the brain by passing strong magnetic pulses through the skull. When applied in trains of pulses it is named repetitive TMS. TMS have been evaluated in 4 randomized control trials in elderly depressed subjects and out of these 3 studies conclude that TMS don't have any beneficial effect at 2 weeks304307. One RCT reported modest positive outcomes on depression in patients with refractory depression and stroke compared with sham treatment307. Course and Outcome of old age depression Course and prognosis of depression have been evaluated in limited number of studies in elderly and there is no consensus regarding the factors which influence the outcome. However it is to be understood that most of the factors which have been linked to outcome and treatment response have been studied in studies with small sample size, varying methodologies, different demographic profiles of the subjects included in the studies and many of these findings have not been replicated. Sociodemographic and social factors: Some studies have reported that older age, women, added supports (aids-hearing, vision), poor perceived health, total number of life events, physical disability and institutalisation are associated with poor outcome309311. On the other hand, studies have also reported that alcohol abuse (Kukull et al, 1986), major life events312, and social factors like education, marital status and social participation don't influence the outcome3'0311. Clinical factors: Studies have reported that presence of chronic physical illness, severe depression, presence of psychotic symptoms is associated with poor outcome and relapse. There have been conflicting results about the relationship between longer duration of current episode and poorer response, with some studies supporting the assertion313315, and some do not9309-168-317. There is conflicting data regarding the presence of comorbid anxiety. Flint and Rifat163 reported that depressed elderly who had high levels of comorbid anxiety symptoms had a lower response rate to nortriptyline and a higher rate of dropping out of treatment. Mulsant et al 3 ' 8 & Dew et al168 found a delayed response (101)
to nortriptyline in depressed elders, if they had a comorbid anxiety disorder or higher self-report anxiety symptoms. However in a recent study, Lenze et al94 didn't find any association between comorbid anxiety and a poorer prognosis during acute treatment of late-life depression. Some neuroimaging studies have reported association between frontal structural changes in brain and response to treatment3'9-320. In another study, a functional neuroimaging study, Navarro et al321 showed that left anterior frontal lobe ratio seems to predict the response to acute pharmacological treatment in late-onset major depression. They found that the risk of non-remission at 3-month followup increased to almost 2.5 times with each extra point in the left anterior frontal lobe ratio. Besides the left anterior frontal lobe ratio other factors which correlated with poorer response were longer duration of current episode and presence of non-endogenous depression. Cognitive functions and outcome of elderly depression: Studies have reported that presence of cognitive dysfunction, especially executive dysfunction predicts poor response to antidepressants. Similarly presence of abnormal initiation/perseveration scores has been linked to increased risk for relapse and recurrence of geriatric major depression322. Based on the findings of executive dysfunction and evidence from neuroimaging, clinical, and neufopathological studies, Alexopoulos et al described a "depression-executive dysfunction syndrome" (DED) of late life.The authors posited that frontostriatal dysfunction (eg, white matter hyperintensities, neuronal and g\\a\ abnormalities in anterior cingulated and dorsolateral cortex) may be etiologically related to both depression and DED and may lead to poor treatment outcome, relapse, and recurrence of symptoms. They also suggested that Problem solving technique might be particularly effective for older DED patients, partly because of their difficulties in abstracting and applying information in novel situations. But there is also data to refute the contention of relationship between executive functioning and relapse, and recurrence of symptoms323. Longest Naturalist Study: In the longest follow up study Heikkinen & Kauppinen324 looked at the changes in depressiveness and the factors related to it. Their results confirmed some of the earlier contentions, which are: 1) mood problems tend to increase in late life specifically among women; 2) in very late life the difference in the level of depression between men and women would, seem to level off; 3) presence of chronic diseases predicted the presence of depression (co-occurrence of just two diseases doubled the risk for depressiveness, when compared to persons with no or just one chronic disease); 4) functional decline was a highly significant risk factor for presence of depressiveness; 5) minor depression among the elderly is most typically a dynamic and episodic phenomenon; 6) Adverse life-events such as the loss of spouse or some other close person, deteriorating health, deteriorating financial situation and increased loneliness had predictive value for depressive symptoms; 7) positive life-changes contribute to improvement in depression scores. Evidence from Meta-analysis: In a meta-analysis, Cole et al325 reported outcome of elderly depressed patients in hospital-based psychiatric services. They found that over a mean 13 to 52 months of follow-up, 60% of the subjects were well (or had relapses with recovery) and only 12%-22% were continuously ill. In another meta-analysis of 12 studies of the prognosis of depression in elderly community and primary care populations, Cole et al325 found that at 24 months after enrollment, 33% were well, 33% were depressed, and 21% had died. Thus, the authors concluded that the prognosis of depression in elderly populations was poor at 24 months after enrollment - almost half of those alive were depressed, probably reflecting the chronic and relapsing course of the disorder. Length of
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follow-up and lower age limit for enrollment was inversely associated with outcome, i.e., length of follow-up and lower age limit for enrollment made it less likely that elderly subjects would be well. Differences in gender distribution, diagnostic criteria, population, or percent receiving antidepressant treatment were not related to outcomes. Authors concluded that the lack of relationship between the percent receiving antidepressant treatment and outcome may reflect the relatively low rates of treatment in these studies. However, this difference in outcome between the primary care population and hospital-based psychiatric services population should be interpreted in the light of fundamental differences between community/primary care subjects and psychiatric patients in the services and treatment provided. Outcome of minor depression: Lyness et al326 compared the outcome of minor depression with major depression and reported that elderly patients with minor or subsyndromal depression have better outcomes than patients with major depression and poorer outcomes than persons who were not depressed.The subjects with minor depression have a risk for a diagnosis of major depression at 1 year, which was more than 5 times greater than that of nondepressed elderly individuals. This finding has importance in providing the basis for prevention. The functional disability of subjects with minor and subsyndromal depression at 1 year was also less than major depression. Indian Research: There are very few studies from India on depression in old age. In majority of the studies the focus has been on evaluation of psychiatric morbidity in community or various special population groups like-those attending geriatric clinics, psychiatric clinics, those admitted in psychiatric inpatient units etc. Only one study tried to evaluate the role of life events in the development of depression in old age. Similarly only 1 study has evaluated the outcome of late onset depression. There are no studies on evaluation of antidepressant efficacy in Indian population. With what ever data is available it can be concluded that depression is the commonest psychiatric morbidity in elderly subjects in our country across various geographical regions. Prevalence: Nandi et al327 studied psychiatric morbidity of the elderly population of a rural community in West Bengal. In a sample of 183 subjects (male 85, female 98) from 2 villages, majority of who came from class IV families (44.2%), they found 60 % of the population to be mentally ill. Women had a higher rate of morbidity than men (77.6% and 42.4% repetitively). There was significantly more morbidity in population in the age group 70-74 and 80+ as compared to normal population. The total mental morbidity rate was as high as 612/1000 population. Depression was the commonest illness of old age in this sample, the rate being 522/1000 population (101 cases out of 112 were diagnosed as cases of depression). Women had a higher rate of depression- 704/1000 population. Another significant finding was high rate of morbidity amongst the widowed persons. Tiwari328 in an epidemiological study evaluated the prevalence of psychiatric morbidity in rural Uttar Pradesh in those aged 60 years or above and ascertained the causative/contributory role of biosociodemographic factors, if any. They found higher prevalence of psychiatric morbidity in the geriatric group (43.32%) than in the nongeriatric group (4.66%). The most common psychiatric morbidity was neurotic depression, followed by manic-depressive psychosis depression, and anxiety state. Psychiatric morbidity was more^prevalent in those who were "socially, economically, and (103)
educationally disadvantaged. Chhabra & Kar329 studied the profile of psychiatric disorders in elderly psychiatric inpatients. In the review of clinical profile of 10 years of inpatients in psychiatry ward they reported that mood disorders were the most common diagnosis (46.5%), followed by dementia (10.8%) and alcohol dependence and related disorders (10.4%). More than one psychiatric diagnosis was found in 26.6% of patients. Physical comorbidity was seen in 42.8% of the patients, and majority of the subjects had multiple diagnoses. Jhirwal et al330 studied the psychiatric morbidity in 100 randomly selected elderly subjects attending geriatric clinic and found that 29% patients suffered from psychiatric illness.The major illnesses were depressive disorders, cognitive impairment and anxiety disorder. Guha & Valdiya33' evaluated psychiatric morbidity amongst the 30 inmates of old age home and compared it with a socio-demographically matched control sample of 30 subjects from the community. The prevalence rate of psychiatric morbidity in the old age home group was 26.7% compared to 10 % in the control group. There was preponderance of widowed females in the old age home sample. Residents living for more than 10 years in old age homes had increased prevalence of psychiatric morbidity, as were the "first borns". Low income was also a possible predisposing factor in increasing the morbidity trend in this group. The most common psychiatric diagnosis was major depressive disorder (13.4%), followed by dementia (6.7%), schizophrenia (3.3%) and OCD (3.3%) in the study group, which was more than in the control group. Most of the sample population also suffered from one or more form of physical disability. Dey et al332 in a prospective cross-sectional observational study on 1586 elderly subjects (age = 60 years), who attended the Geriatric Clinic of the All India Institute of Medical Sciences, New Delhi found multiple chronic illnesses, frequent acute illnesses and deficits of vision and hearing as the major health and functional problems of the health-seeking older population. In a subset of 209 subjects, they found that about one-third of subjects had a psychiatric illness, depression being the most common (50%) of all psychiatric illnesses. Raichandani et al (2004)333 screened 100 geriatric patients attending the geriatric medical OPD for depression and compared subjects with and without depression and found that the depressed subjects were relatively younger, less educated, belonged to middle socio economic class with poor financial and family support. The depressed subjects also did not involve them selves in activities like exercising, socializing etc., compared to non depressed group. In a study on morbidity profile and its relationship with disability and psychological distress, Joshi et al334from Chandigarh found that among all the symptoms, depressive symptoms in the form of feeling of sadness was 'he most common symptoms, reported by 70.5% of the subjects. They also found that there was an inverse relationship between number of physical morbidities and psychological well being and the disability increased with decrease in psychological well being. Etiology: Agarwal & Jhingan335 studied the role of life events in old age depression in a cross-sectional hospital based study of 31 elderly depressive patients (diagnosed as suffering from depressive episode or recurrent depressive disorder according to ICD-10 DCR) attending psychiatry O.P.D. or geriatric clinic at the All India Institute of Medical Sciences, New Delhi (AIIMS) and compared it with 31 elderly nonpsychiatric patients, attending geriatric clinic at AHMS.They reported that elderly depressed patients experienced significantly higher number of stressful life events as compared to the control
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group. The stressful life events were specifically more in the females, and in those with low 'per capita income', and those who perceived crisis in the family. Perception of family support was found to be poorer in the case group as compared to the control group though the difference was not significant. Similarly, a greater proportion of case group subjects reported some crisis in the family as compared to controls. Prevalence of physical illnesses in elderly depressed subjects: Satapathy et al336 evaluated the prevalence of physical illnesses in 40 elderly depressed subjects and compared with a control group of 20 elderly subjects without psychiatric morbidity from general population. Multiple illnesses were present in 90% of the study group, in contrast to only 20% in tne control group. The most common system involved was musculoskeletal followed by cardiovascular and ophthalmological systems. The common diagnoses in order of frequency were osteoarthritis 77%, hypertension 55%, cataract 47%, chronic respiratory disease 25%, ischaemic heart disease 17% and diabetes mellitus 12%. Amongst these, hypertension, osteoarthritis and cataract were significantly more in the study group compared to the control group. The physical disabilities like impairments of locomotion and vision were found in about 60% of patients and were significantly more in patient group than in controls. According to the authors 67% of the study sample the physical illnesses and disabilities had an aggravating role in depression, while in 7% depression was possibly secondary or unrelated. Out of the all physical morbidity, in 76 % of elderly depressed subjects the physical illnesses were previously undiagnosed compared to 71 % in control group. Hindi adaptation and application of GDS: Ganguli et al337 developed a Hindi version of the Geriatric Depression Scale and administered the same to 1554 mostly illiterate Hindi-speaking residents' participants in rural community of Ballabgarh in northern India. They found that the Hindi version of the Geriatric Depression Scale (GDS-H) had high internal consistency and a factor structure comparable to the original English language version. The overall distribution of scores was higher than reported from other populations. Higher scores on the GDS-H were associated with older age and illiteracy. Among the illiterate, there was no gender difference while among the literate, higher GDS-H scores were found among women. Cognitive impairment and functional disability were independently associated with higher scores on the GDS-H after adjustment for age, gender and literacy. Sociodemographic & Clinical Profile: Chakrabarti et al338 compared the clinical and psycho-social profile of 31 elderly depressed subjects in a hospital unit with 30 younger patients with depression. The authors found that the sociodemographic and clinical profile of patients in both the groups was similar. Patients in both the groups reported poor perceived support, an excess of undesirable life events before their episode and significant dysfunction. In another study, Jain et al339 assessed the sociodemographic and clinical profile of elderly patients attending a psychiatric clinic in a tertiary hospital setting. Out of the 109 patients >60 years attending the psychiatry OPD, majority of the subjects were between 60 and 70 years of age (69.7%), males (60%) and married (76%). Majority of the sample was illiterate (40%), belonged to the low socioeconomic status (50%), joint families (47%) and came from an urban locality (70%). The major diagnostic category was depressive disorders. Thirty per cent were suffering from physical co-morbidity. Raichandani et al (2004) screened 100 geriatric patients attending the geriatric medical OPD. They found that 63 % of the subjects fulfilled the criteria of depression. Perception and attitude about mental illness: In another study Patel & Prince340, in a study from
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Goa on cultural perceptions of mental illnesses and care arrangement for older people found that depression was a common presentation in primary care, but was infrequently diagnosed. Depression and dementia were attributed to abuse, neglect, or lack of love on the part of children towards a parent. They also found that the system of family care and support for older persons was less reliable than has been claimed. Care was often conditional upon the child's expectation of inheriting the parent's property. It was also observed that those who had dependency needs, their care were almost entirely family-based with little or no formal services. The authors concluded that there is a need to raise awareness about mental disorders in late-life in the community and among health professionals, and to improve access to appropriate health care for the elderly with mental illness. Prognosis of late-onset depression: Jhingan et al341 studied the 12-month outcome of late onset depression and found that at the end of 1 year 28 % of the patients had recovered, 30% had partially recovered, 23% had relapsed, 6% had been continuously ill, 11% had died, and 6% had developed comorbid dementia. The authors concluded that overall, the 12-month outcome was poor in elderly individuals with late-onset depression.They also reported that the subjects who had shorter duration of episode at the baseline assessment and who were living in joint family system had good outcome. ECT: In a survey of practice of electroconvulsive therapy in teaching hospitals in India, Chanpattana et al342 found that subjects aged more than 65 years of age formed the third largest group of subjects who were administered ECT in various teaching hospitals in India. Although data specific to elderly was not available, but overall depression was the second most common reason (after schizophrenia) for which ECT was used. Side effects of antidepressants: As discussed earlier there are no systemic studies which have evaluated the efficacy of antidepressants in elderly population. However, there are case reports which have reported side effects with antidepressants. Case reports of SIADH with use of escitalopram and citalopram in elderly subjects have been reported343345. Ghorpade et al346 reported two cases of pseudo-intestinal obstruction in patients receiving antidepressants. One patient was receiving amitriptyline 150 mg/day and fluoxetine 40 mg per day. Another patient was receiving a combination of clomipramine 50 mg /day and nitrazepam 10 mg/day. Recommendations for Clinical Practice The treatment recommendations that follow are for elderly depressed patients. As discussed above, as most of the literature is available in relation to major depression, recommendations refer to patients with major depressive disorder, minor depression and to some extent to dysthymia in elderly. The first step of treatment plan comprises of a through assessment. As in young adults the treatment consists of three phases of treatment - acute phase, continuation phase and maintenance phase. Assessment The assessment process not only involves establishing the diagnosis, but it also should take intu consideration, factors like how much is the risk to life of patient and how much is the dysfunction. It also involves establishing a good therapeutic alliance with the patient and making decision about treatment setting and patient's safety. In the following section all these issues are discussed. The most important aspect of assessment is that the clinicians understanding of the fact that assessment is not a one step process, but it is a continuous process and patient should be assessed regularly, as per the need and phase of the treatment.
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1.
Perform a diagnostic evaluation Patients with depressive symptoms should be evaluated thoroughly to determine whether a diagnosis of depression is warranted and for the presence of other psychiatric or general medical conditions. The complete psychiatric evaluation should include a history of the present illness and current symptoms; a psychiatric history, including symptoms of mania as well as a treatment history that particularly notes current treatments and responses to previous treatments; a general medical history and history of substance use disorders; a personal history (e.g., psychological development, response to life transitions, and major life events); a social, occupational, and family history; a review of the patient's medications; a review of systems; a mental status examination; a physical examination; and diagnostic tests as indicated. While evaluating for depression in elderly it is important to remember that elderly depressed patients tend to report more somatic and cognitive symptoms than affective symptoms. It has been reported that men are less likely to report mood-related symptoms than women348. Some patients also often misattribute symptoms of depression to normal aging or medical illness349. It is often misattribution shared by patients, families, and providers that reduces chances for effective treatment. Patients who deny having depressed mood may report a lack of feeling or emotion or acknowledge a loss of interest and pleasure in activities. The tendency of elderly depressed patients to report fewer affective symptoms has been labeled as "depression without sadness"2. This concept encompasses a variant of depression, specifically seen in elderly primary care populations and consists of apathy, loss of interest, fatigue, difficulty sleeping, and other somatic symptoms, but not sad mood. However, it is unclear whether "depression without sadness" is an idiopathic depression, a depression secondary to medical illness, or a nonaffective syndrome related to chronic medical disease. Another important aspect to remember while carrying out the diagnostic evaluation is the relationship between depression and medical illnesses. Studies have shown that increased medical burden increases depressive symptoms at least temporarily350 and long-term depressive symptoms increase medical burden350 and mortality351353. The diagnosis of "depression due to a general medical condition" can be used for medical illnesses with a known etiologic link to depression. But at large, this term is irrelevant to the large number of elderly patients in whom overall medical burden contributes to their depression354357. Physiologic stress of illness, functional disability, and life changes necessitated by chronic illness may precipitate depression in susceptible individuals354358. Reciprocal patterns of causation are also common in late-life depression associated with medical comorbidity, for example, depression may amplify the perception of pain, and persistent pain worsens depression. Because of the comorbidity the elderly subjects are often on multiple drugs, hence it is very important to trke a detailed drug history, as many drugs have been reported to cause depression. However it is important to remember that with few exceptions (e.g. corticosteroids, interferon), evidence regarding the magnitude of affective risk attributable to specific medications is inadequate and perhaps overstated359'361. Nonetheless, examining the temporal course of medications and depressive symptoms can be helpful in making treatment decisions (e.g., drug discontinuation) in individual patients. Due to overlap of depressive symptoms and symptoms due to medical illnesses various approaches have been used for the identification of depressive symptoms in the elderly. The "exclusive approach" would not classify neurovegetative symptoms (e.g., changes in sleep, energy, (107)
appetite, and weight) as part of the depression syndrome. The "substitutive approach" ignores neurovegetative symptoms but introduces nonsomatic cognitive symptoms (e.g., hopelessness) when defining a major depressive episode. The "best estimate approach" demands that for each symptom a clinical judgment is made as to whether the symptom is caused by a physical disoraer or is part of a depressive syndrome. Finally, the "inclusive approach" assumes that all depressive symptoms contribute to the syndrome, regardless of their causes 355362 ' 365 . Given the underrecognition of depressive disorders, an inclusive approach to diagnosis may be preferable in older medically ill patients355 362365. Nonetheless, the various contributors to depressive symptoms (e.g., medical causes) need to be considered to avoid offering unnecessary treatment. Another important confounder of diagnosis of depression in elderly subjects is dementia. Some symptoms of depression overlap with behavioral manifestations of dementia, including apathy and loss of initiative366369. In some demented patients, particularly those without history of mood disorders, depressive symptoms fluctuate over time or fail to meet criteria for intensity, duration, or functional impact required for a diagnosis of major depression. Furthermore, the expression of depressive syndromes may change with the progression of Alzheimer's disease370.The diagnosis of depressive syndromes in demented patients also varies markedly depending on whether it is based on reports from patients, caregivers, or trained observers 355.369,371,372 purther, the patient inability to communicate coherently forces diagnostic and treatment decisions to be made on the basis of behavior alone; however, psychomotor slowing, emotional lability, crying spells, insomnia, weight loss, inability to verbalize affective state, and pessimism occur in depressed and nondepressed demented patients373. Depressed Alzheimer's patients display more self-pity, rejection sensitivity, and anhedonia and fewer neurovegetative signs than non-demented depressed older patients374. Rating scales have been developed to discriminate between depressed and nondepressed demented patients366369. Combining patient interview with information obtained by caregivers and using depression scales that focus on symptoms not shared by the depression and the dementia syndromes has been found to be a reliable and valid assessment method366. As it has been reported by various researchers that the DSM-IV criteria capture a minority of depressed demented patients, the National Institute of Mental Health has developed provisional diagnostic criteria for depression of Alzheimer's disease which requires empirical validation and refinement375-376. The following provisional criteria are similar to the DSM-IV criteria for major depression, with changes addressing the special characteristics of depression of Alzheimer's disease: 1) the provisional criteria require three or more symptoms of depression, instead of the five symptoms required for idiopathic major depression; 2) the criteria include irritf' '''••/ and social isolation or withdrawal on the list of depressive symptoms; 3) the criteria include "dccr°r. ..ed positive affect or pleasure" instead of loss of interest or pleasure; and 4) the criteria require that the symptoms have been present during the same 2-week period and represent a change from previous functioning but no longer require that symptoms occur nearly every day. Another important aspect for evaluation of depression in elderly is look for nutritional deficiencies which may be responsible for the depressive symptoms and just correction of the same may be sufficient. 2. Assessment of cognitive functions
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Besides doing the diagnostic evaluation and workup it is very important to assess the cognitive functions of elderly subjects presenting with depressive symptoms as some times the depressive symptoms may be first manifestation of early dementia. The relationship between depression and cognitive deficits can be understood from 3 prospective, i.e., memory loss can lead to depression; depression can be accompanied by cognitive impairment that is reversible, at least temporarily, in that it lifts when the depression is treated; and depression can co-occur with dementia, where depression represents a prodromal symptom, a comorbid condition possibly reflecting similar physiological factors, or a reaction to the dementia. The cognitive function assessment can be done at bedside or the outpatient clinic by using MMSE. If required a complete battery of organic brain syndrome should be used. 3.
Investigations In contrast to young adults, all the elderly subjects should be investigated. In general the list of investigations would be guided by the physical evaluation and history of medical illness. But if at all there is no historical evidence of medical illness and nothing significant is found in physical examination to warrant lab investigation, then also the elderly patients should be subjected to a minimum battery comprising of heamogram, liver function tests, renal function tests, urine analysis and electrocardiography (ECG). Some authors31 also advise to include thyroid function tests, Vitamin B12 and folate levels and medication levels, which patient is receiving. However, these tests may not be feasible in Indian setting for because of reasons like availability of these tests and financial.
4. Evaluate the safety of patient and others Compared to young adults, elderly subjects, especially males are at increased risk of completed suicide. Aging reduces suicide attempts but increases their lethality377378. Hence, a careful assessment of the patient's risk for suicide should be carried. During history taking the clinicians should enquire for the presence of suicidal ideation and other associated factors like presence of psychotic symptoms, severe anxiety, panic attacks and alcohol or substance abuse which increase the risk of suicide. It has been found that severity of depressive symptomatology is a strong predictor of suicidal ideation over time in depressed elderly patients379. Due to the same, beyond examination of suicidal ideation and availability of means of suicide, clinicians should rely on the severity of depressive symptoms for assessing the potential for suicide. Evaluation should also include history of past suicide attempts including the nature of those attempts. Patients should also be asked about suicide in their family history and recent exposure to suicide or suicide attempts by others. During the mental status examinations besides enquiring about the suicidal ideations, it is also important to enquire about the degree to which the patient intends to act on the suicidal ideation and the extent to which the patient has made plans or begun to prepare for suicide. The availability of means for suicide should be inquired about and a judgment made concerning the lethality of those means. Patients who are found to possess suicidal or homicidal ideation, intention or plans require close monitoring. Measures such as hospitalization should be considered for those at significant risk. The various risk factors or predictors of suicide, especially in elderly m*°w are shown in table-19. Table -19 : Risk factors for elderly Suicide (109)
1. Older age 2.
Male gender
3. Living alone 4.
Bereavement, losses
5. Comorbid - alcohol misuse 6. Chronic Pain 7.
Previous history of suicide attempt
5. Evaluate the dysfunction Depression is frequently associated with significant dysfunction, and the presence, type, and severity of dysfunction should be evaluated. Impairments can include deficits in interpersonal relationships, work, living conditions, and other medical or health-related needs. Identified impairments in functioning should be addressed. Patients should also be encouraged to set realistic, attainable goals for themselves in terms of desirable levels of functioning. 6. Determine a treatment setting Treatment setting for patients with depression includes a continuum of possible levels of care from involuntary hospitalizations to outpatient settings. In general, the rule of thumb should be that the patients should be treated in the setting that is most safe and effective. The decision of the clinician should be based on patient's clinical condition, including symptom severity, comorbidity, suicidality, homicidality, level of functioning and available support system. It should also take into consideration the ability of a patient to adequately care for themselves, provide information about the health status to the clinician and cooperate with treatment. Patients who exhibit suicidal or homicidal ideation, intention or a plan require close monitoring. Hospitalisation is usually indicated for patients who are considered to pose a serious threat of harm to themselves or others. Severely ill patients who lack adequate social support outside of a hospital setting should be considered for admission to a hospital. Additionally, those patients who also have complicating psychiatric or general medical conditions or who have not responded adequately to outpatient treatment may need to be hospitalized. The patients who should be considered for inpatient setting treatment are shown in table-20. The optimal treatment setting and the patient's ability to benefit from a different level of care should be re-evaluated on an ongoing basis throughout the course of treatment. Table-20: Indications for admission in elderly patients with depression 1. Those who express suicidal ideas of a definite sort, or who have made a attempt suicide 2. Those who harm themselves, or threaten to, for the first time (especially men) 3. Subjects who have problems with treatment compliance or delivery, leading to unduly protracted treatment 4. Those who require electroconvulsive therapy 5. Those wn. gleet themselves substantially, particularly their fluid intake 6. Those who require removal from a hostile social environment
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7. 8. 9. 10.
Those who are in such distress as to need tranquillisation or skilled nursing care Those who have physical illness that is complicating treatment Those who have not responded adequately to outpatient treatment Frail elderly
7. Establish and maintain a therapeutic alliance Regardless of the treatment modalities ultimately selected for patients, it is important for the clinicians to establish a therapeutic alliance with the patient. Depression is often a chronic condition and it requires patients to actively participate and adhere to treatment plans for long periods. In addition, successful treatments may require patients to tolerate some side effects. For these reasons, a strong treatment alliance is crucial. The most important component of the therapeutic alliance is that pays attention to the concerns of patients and their families as well as their wishes for treatment. Management of the therapeutic alliance should also include awareness of transference and counter-transference issues, even if these are not directly addressed in treatment. 8. Monitor the patient's psychiatric status and safety In the due course of treatment, different features and symptoms of the patient's illness may emerge or subside. Monitoring the patient's status for the emergence of changes in destructive impulses towards self or others is especially crucial. Additional measures such as hospitalization or more intensive treatment should be considered for patients found to be at higher risk. Significant changes in a patient's psychiatric status or the emergence of new symptoms may warrant a diagnostic re-evaluation of the patient. 1.
Psycho-educate the patient and family Education concerning depression and its treatments should be provided to all patients. When appropriate, education should als/a be provided to involved family members. Specific educational elements may be helpful in some circumstances, e.g. that depression is a real illness and that effective treatments are both necessary and available may be crucial for patients who attribute their illness to a moral defect or witch craft. Education regarding available treatment options will help patients make informed decisions, anticipate side effects and adhere to treatments. Another important aspect of providing education is informing the patient and especially family about the lag period of onset of action of antidepressants.
10. Enhance treatment adherence The successful treatment of depression requires close adherence to treatment plans, sometimes for long or indefinite durations. Especially, symptomatic patients may be poorly motivated, unduly pessimistic over their chances of recovery with treatment, suffering from deficits in memory or taking less care of themselves. Further, elderly patients may attach a stigma to depression, disagree with clinicians when informed of their diagnosis, and be concerned about the impression they make to their families382. They often fear that antidepressants are addictive or interfere with treatment of their medical disorders383. Side effects of treatments may contribute to non-adherence. During the maintenance phase, euthymic patients may tend to undervalue the benefits of treatment and focus on its burdens. Specific components of a message to patients that have shown to
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improve adherence include: when and how often to take medicine, the need for at least 3-4 weeks before beneficial effects are noted, the need to take medication even after feeling better, the need to consult the doctor before discontinuing medication, what to do if problems or questions arise. Elderly patients have shown to improve adherence when the complexity of regimens and the costs of treatments are reduced. Severe or persistent problems of non-adherence may represent psychological conflicts or psychopathology for which psychotherapy should be considered. Family members can play helpful role in improving adherence. 11. Work with the patient to address early signs of relapse Fluctuation of symptoms is common in depression and patients and their families should be educated about the significant risk of relapse. They shou!., be educated to identify the early signs and symptoms of new episodes. Patients should also be asked to seek adequate treatment as early in the course of a new episode as possible to decrease the likelihood of a full-blown relapse or complication. ACUTE PHASE TREATMENT The goals of acute phase treatment should be to achieve remission, as presence of residual symptoms increase the risk of chronic depression and also impairs recovery from physical illness. Treatment should generally result in improved quality of life, enhanced functional capacity, and possible improvement in medical health status and increased longevity. Selecting initial treatment modality: Choosing the most suitable treatment modality for elderly depressed subject from the treatment armamentarium should be based on clinical severity of symptoms, past and family history, comorbidity (physical and psychiatric), medications which he is already receiving and patient's preference. The elderly typically display more vegetative signs and cognitive disturbance and complain less of subjective dysphoria than do their younger counterparts; major depressive disorder may consequently be misattributed to physical.illness, dementia, or the aging process itself. It is recognized, however, that major depressive disorder and general medical illness frequently coexist in this age group, and those undergoing their first major depressive disorder episode in old age should be regarded as possibly harboring an as yet undiagnosed neurological or other general medical disorder that is responsible for the major depressive disorder condition. In subjects who are already on certain medications, the clinician should carefully assess whether a given agent contributed to the major depressive disorder before prematurely altering what may be a valuable medication regimen. Major depressive disorder is a common complication of cerebral infarction, especially in the anterior left hemisphere. Antidepressant medications can be used as an initial treatment modality for patients with mild, moderate, or severe major depression. Clinical features that may suggest that medications are the preferred treatment modality include history of prior positive response to antidepressant medications, severity of symptoms, significant sleep and appetite disturbances or agitation, or anticipation of the need for maintenance therapy. Other issues that may be important considerations in the decision to use antidepressant medication include patient preference or the lack of available adequate alternative treatment modalities. Patients with major depression with psychotic features require either the combined use of antidepressant and antipsychotic medications or ECT. A specific, effective psychotherapy alone may be considered as an initial treatment modality for patients with minor
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depression and mild to moderate major depression. Clinical features that may suggest the use of a specific psychotherapy include the presence of significant psychosocial stressors, intrapsychic conflict, interpersonal difficulties, or axis II comorbidity. Patient preference for psychotherapeutic approaches is an important factor that should be considered in the decision to use psychotherapy as the initial treatment modality. The combination of a specific effective psychotherapy and medication may be a useful initial treatment choice for patients with psychosocial issues, intrapsychic conflict, interpersonal problems, or a comorbid axis II disorder together with moderate to severe major depressive disorder. In addition, patients who have had a history of only partial response to adequate trials of single treatment modalities may benefit from combined treatment. Poor adherence with treatments may also warrant combined treatment with oharmacotherapy and psychotherapeutic approaches. ECT should be considered for patients with major depression with a high degree of symptom severity and functional impairment as well as in cases in which psychotic symptoms or catatonia are present. ECT may also be the treatment modality of choice for patients in whom presence of comorbid general medical conditions preclude the use of antidepressant medications, there is an urgent need for response, such as patients who are suicidal, who are refusing food and are nutritionally compromised and have a past history of positive response tc ECT. The patient preference is another important consideration that may influence the decision to select ECT as a treatment modality. However it is to be remembered that ECT is contraindicated in recent myocardial infarction, brain tumor, cerebral aneurysm, and uncontrolled heart failure. Figure 1 and 2 depict the treatment algorithms for depression of different severity. Selecting a specific antidepressant: The selection of antidepressant medications should be based on patient specific and drug specific factors, as given in table-21 .The patient specific factors include patient preference, previous history of response/ tolerability to medication in the patient or family member, patient's age, comorbid medical illness, comorbid psychiatric disorder/symptoms, other medication being taken, sexual dysfunction and intellectual and psychological capacities. The drug specific factors include the anticipated side effects, the safety or tolerability of these side effects for individual patients, cost, dosing schedule, type of formulations available and safety in overdose. Elderly people are generally more susceptible to anticholinergic effects, and the newer antidepressants should therefore be preferred. If a tricyclic antidepressant has to be used, drugs with pronounced anticholinergic effects, such as amitriptyline, should be avoided. Other medications which should be avoided include those causing hypotension, and those with highly sedating properties. Table-21: Factors that determine the selection of Antidepressant Drug Patient specific • Patients preference • Previous history of response/tolerability to medication in the patient or family member • Past side effects with medication • Other medication being taken - drug interactions • Patient's age - with increasing age the pharmacokinetic and pharmacodynamic changes become more important • Comorbid medical illness (e.g., glaucoma, cardiac conditions) • Comorbid psychiatric disorder/symptoms • Gender issues - sexual dysfunction • Intellectual and psychological capacities
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Drug Drug specific • Side effects • Cost • Dosing strategy • Type of formulation - Tablet, Cap, Syrup • Safety in overdose (Relative Toxicity) - fatal overdose is significantly lower with SSRIs than with tricyclic antidepressants Among the cyclic compounds, desipramine is less sedating and can be taken during the day, and nortriptyline is less likely to cause orthostatic hypotension than amitriptyline or imipramine. Although MAOIs are thought to be dangerous and difficult to use, drugs such as phenelzine are relatively safe and effective in older patients. Hypotension, hypertension, and food-drug interactions are the most likely problems with MAOI use. Moclobemide is well tolerated by older people. Although a special diet is not required, patients should be a w e of the drug interactions with painkillers and other antidepressants. Blood pressure moniton.ig is necessary with venlafaxine in patients with preexisting cardiovascular disease and patients taking relatively high dosages. Nefazodone works well in patients with anxiety and depression. Rarely nefazodone may lead to agitation and sexual dysfunction. However, use of nefazodone has been associated with liver failure, and the drug has been taken off the market in Europe and Canada. Other drawbacks of nefazodone include twice-daily dosing, sedation, and drug interactions. Gastrointestinal symptoms are well recognized side effects of SSRIs. Among the SSRIs sertraline and citalopram have the least potential for drug interactions. For clinicians it is important to remember that the antidepressant effect may be more delayed in elderly people than in younger subjects, and treatment may need to be continued for longer than six months. Different antidepressants and their dose range for geriatrics patients is given in table -22. As discussed the general principle of starting antidepressants in elderly should be "Start low and go slow". As per the evidence there is no support to suggest that a particular drug should be tried before trying another, but in practice, most experts prescribe selective serotonin reuptake inhibitors (SSRIs) as the first agent31. Once an antidepressant medication has been selected it can be started at doses suggested in table22. Titration of the dose to full therapeutic doses generally can be accomplished over the initial weeks of treatment but may vary depending on the development of side effects and the presence of comorbid conditions. It has been suggested that the dose should be increased if patient compliance is good and there is no response after three weeks. If there is a partial response, another two weeks could be waited before increasing the dose. Clinicians should also reassure patients that they may feel worse before they start to feel better. Patients who have started taking an antidepressant medication should be carefully monitored to assess the response to pharmacotherapy as well as the emergence of side effects, clinical condition, and safety. Visits should be frequent enough to monitor and address suicidally and to promote treatment adherence. In clinical practice, the frequency of monitoring during the acute phase of pharmacotherapy should vary from once a week in routine cases to multiple times per week in more complex cases. Optimally, if the selected drug yields no side effects, subjective improvement is felt at about 3 to 4 weeks. The signs of effectiveness include improvements in appetite, interest in doing things, mood, sleep, and less sadness or anger. Some note a feeling of contentment with the SSRIs and state that things just do not bother them anymore.
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Although there is no consensus, but most experts agree that older subjects would require longer time than young adults to perceive any improvement and to perceive moderate improvement pharmacotherapy would take 4-8 weeks of treatment, but 2 to 3 months of therapy are necessary to achieve the full benefit of treatment. The deiayed clinical response to antidepressants makes it difficult to establish the optimal dose quickly. The individual dose is usually decided by trial and error. The patient is usually the last to notice a change, and others often will tell the person that he/she looks better than before. At least 30% of elderly patients with depression do not respond to first-line treatment with an antidepressant137. If at least moderate improvement is not observed following 4-8 weeks of pharmacotherapy, a reappraisal of the treatment regimen should be conducted. First, patient adherence and pharmacokinetic/pharmacodynamic factors affecting treatment should be investigated. Following this review, the treatment plan can be revised by implementing one of several therapeutic options, including maximizing the initial medication treatment, switching to another antidepressant medication, augmenting antidepressant medications with other agents or psychotherapy, or ECT. Maximizing the initial treatment regimen is perhaps the most conservative strategy. As discussed above, for patients who show partial response, particularly those with features of personality disorders, antidepressant medication trial should be extended as it may allow some patients to respond more fully. Use of higher antidepressant doses may be helpful for patients who have received only modest doses. Patients who have had their dose increased should be monitored for an increase in the severity of side effects. Switching to a different antidepressant medication is a common strategy for treatment-refractory patients, especially those who have not shown at least partial response to the initial medication regimen. There is no consensus about switching and patients can be switched to an antidepressant medication from the same pharmacologic class (e.g., from an SSRI to another SSRI) or to one from a different pharmacologic class (e.g., from an SSRI to a tricyclic antidepressant). Some expert suggests that while switching, a drug with a different or broader mechanism of action should preferably be chosen. While switching to a second antidepressant, clinicians should remember that there is some evidence to suggest that venlafaxine may be useful in cases, who don't respond to initial pharmacotherapy. Augmentation of antidepressant medications may be helpful, particularly for patients who have had a partial response to initial antidepressant monotherapy. Options include adding a second antidepressant medication from a different pharmacologic class, or adding another adjunctive medication such as lithium, psychostimulants, modafinil, thyroid hormone, an anticonvulsant etc. Adding, changing, or increasing the intensity of psychotherapy should be considered for patients with major depressive disorder who do not respond to medication treatment. Following any change in treatment, the patient should continue to be closely monitored. If there is not at least a moderate improvement in major depressive disorder symptoms after an additional 4-8 weeks of treatment, the psychiatrist should conduct another thorough review. This reappraisal should include verifying the patient's diagnosis and adherence; uncovering and addressing clinical factors that may be preventing improvement, such as the presence of comorbid general medical conditions or psychiatric conditions (e.g., alcohol or substance abuse); and uncovering and addressing psychosocial issues that may be impeding recovery. If no new information is uncovered to explain the patient's lack of adequate response, ECT should be considered. Choice of a specific psychotherapy: The potential benefit of psychotherapy is not diminished by increasing age. There is evidence that for older adults with mild-to-moderate depressive episodes a
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psychological intervention is as effective as medication'37 3e4. Some studies have also suggested that older adults often have better treatment compliance, lower dropout rates, and more positive responses to psychotherapy than younger patients. Out of the various psychotherapeutic models used in elderly, cognitive behavior therapy (CBT) and interpersonal psychotherapy (IPT) have been found to have sufficient evidence. However, it is to be remembered that most studies have looked at their use in cognitively intact and medically stable patients and so its effectiveness outside this patient group is not fully established. Small studies and case reports have indicated that CBT can be adapted for use with physically frail patients and those with mild cognitive impairment, but further research is needed. The major determinants of type of psychotherapy are patient preference and the availability of clinicians with appropriate training and expertise in specific psychotherapeutic approaches. Other clinical factors influencing the type of psychotherapy employed are the stage and severity of the major depressive disorder episode. Psychotherapy is usually recommended 'or elderly patients with depression who have evidence of stressful life events, family conflicts, anr te reduction or absence of social support. In general, in a country like India, the choice among psychotherapeutic approaches is dependent on the clinicians training and expertise in specific psychotherapeutic treatment. Besides the use of specific psychotherapeutic approaches as enumerated above the clinicians can also use psycho-educational approach and supportive psychotherapy techniques which also have preliminary evidence to be effective. In general the basic principle which should guide any kind of supportive psychotherapy and psychoeducational model should be use of adaptive strengths that have served the patient well in the past, increasing the patient's self-esteem, accepting feelings at face value, holding the prospect of hope, accepting anger and irritability and avoiding imposing a new lifestyle. When psychotherapy is part of the treatment plan, it must be integrated with other treatment strategies which patient may be receiving. The optimal frequency of psychotherapy has not been rigorously studied in controlled trials. The clinicians should take into account multiple factors when determining the frequency for individual patients, including the specific type and goals of the psychotherapy, the frequency necessary to create and maintain a therapeutic relationship, the frequency of visits required to ensure treatment adherence, and the frequency necessary to monitor and address suicidality. Also affecting the frequency of psychotherapy visits are the severity of illness, the patient's cooperation with treatment, the availability of social supports, cost, geographic accessibility, and presence of comorbid general medical problems. Regardless of the type of psychotherapy selected, the patient's response to treatment should be carefully monitored from the outset of psychotherapy. If the patient's condition fails to stabilize or is deteriorating, reassessment is indicated. If after 4-8 weeks of treatment at least a moderate improvement is not observed, then a thorough review and reappraisal of the diagnosis, complicating conditions and issues, and treatment plan should be conducted. In many cases, the treatment plan can be revised by the addition or substitution of pharmacotherapy. Following any revision or refinement of treatment, the patient should continue to be closely monitored. Medications plus psychotherapy: Preliminary data suggests that combined treatments are better than monotherapies in the treatment of late-life depression. However, there are very few studies in this area and selection of combination of particular antidepressant medications and psychotherapeutic approaches for individuals who will receive the combination of both modalities should depend upon the same issues that influences these decisions when choosing a monotherapy, and the same doses of antidepressant medication and the same frequency and course of psychotherapy should be used for patients receiving combination modality treatments as those employed for patients receiving them as a monotherapy.
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Patients receiving combined antidepressant medication and psychotherapy should also be monitored closely for treatment effect, side effects, clinical condition, and safety. If after 4-8 weeks there is not at least a moderate improvement, a thorough review should be conducted, including of the patient's adherence and pharmacokinetic/pharmacodynamic factors affecting treatment. The treatment plan can be revised by using many of the same therapeutic options described for patients who have not responded to treatment with either modality alone. Following any change in treatment, the patient should continue to be monitored, and if there is not at least a moderate improvement in major depressive disorder symptoms after an additional 4-8 weeks of treatment, another thorough review should be conducted. CONTINUATION PHASE During the continuation phase, patients who have been treated with antidepressant medications in the acute phase should be maintained with these agents to prevent relapse. In general, the same dose should be continued. Although there is scarcity of data about use of psychotherapy in the continuation phase to prevent relapse, some experts support the use of a specific effective psychotherapy during the continuation phase. Use of ECT in the continuation phase has received little formal study. There is no consensus on the duration of continuation phase in elderly, but some experts suggest that treatment should be continued for 1 year after remission.The frequency of visits must be determined by the patient's clinical condition as well as the specific treatments being provided. For stable patients in whom the visits are for the purpose of providing psychiatric management, the frequency could be once every 2 weeks to 2 months. For other patients, such as those in whom active psychotherapy is being conducted, the frequency required may be as high as multiple times a week. If maintenance phase treatment is not indicated for patients who remain stable following the continuation phase, patients may be considered for discontinuation of treatment. If treatment is discontinued, patients should be carefully monitored for relapse, and treatment should be promptly reinstituted if relapse occurs. Figure -3 shows the treatment algorithm for continuation phase of treatment. MAINTENANCE PHASE As in young adults, depression has a strong tendency to recur in elderly persons, with rates of recurrence of 50 to 90 percent over a period of two to three years; hence, the goal of treatment should be not only recovery from current episode, but also the prevention of recurrence. There is no consensus regarding the duration and when to give and when not to give maintenance treatment in elderly. There is agreement to large extent that patients who have history of three or more relapses or recurrences should be given long-term treatment (Alexopoulos et al, 2001), but maintenance treatment for 2 episodes is still debated. The principles of management during maintenance phase should be on the similar lines as with young adults. Therefore, following the continuation phase, maintenance phase treatment should be considered for patients to prevent recurrences of major depressive episodes. In general, the treatment that was effective in the acute and continuation phases should be used in the maintenance phase. The same full antidepressant medication doses should be used. For psychotherapy during maintenance phase, treatments can involve fewer visits (e.g., once a month). Although the effectiveness of combinations of antidepressant medication and psychotherapy in the maintenance phase has not been well studied, such combinations may be an option for some patients. The frequency of clinic visits in maintenance phase can vary from once every several months for stable patients who require only psychiatric management and medication monitoring to as high as once or twice per week in
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those who are either receiving psychotherapy or severely medically compromised. The optimal length of maintenance treatment is not known and may also vary depending on the frequency and severity of recurrences, tolerability of treatments, and patient preferences. For some patients, maintenance treatment may be required indefinitely. Figure -4 shows the algorithm for maintenance phase.. Clinical Features that require special attention 1.
Suicide risk Elderly patients with major depressive disorder are at greater risk for suicide. Suicide risk should be assessed initially and over the course of treatment. The major social and demographic risk factors for suicide among the elderly are include old age, male gender, and unmarried status38038129. Some studies have shown that generally, the suicidal patients are suffering from first episode of major depression, which is moderately severe, yet the depressive symptoms have gone unrecognized and untreated386. Another important thing to remember is that most elderly persons who commit suicide communicate their suicidal thoughts to family or friends before killing themselves29 and more than 75% of these individuals visit a primary care physician about general medical problems and somatic complaints less than one month prior to their suicide380386"388, 39% the week before380. Hence it is very important to enquire about suicidal ideations at every visit. If the patient has suicidal ideation, intention, or a plan, close surveillance is necessary. Factors to be considered in determining the nature and intensity of treatment include the nature of the doctor-patient alliance, the availability and adequacy of social supports, access to and lethality of suicide means, and past history of suicidal behavior. The risk of suicide in some patients recovering from major depressive disorder increases transiently as they develop the energy and capacity to act on self-destructive plans made earlier in the course of their illness. In patients those who have suicidal ideation, intention and past history of suicidal behaviour, have family history of suicide should preferably be managed in inpatient setting.
2.
Psychotic features Major depressive disorder with psychotic features carries a higher risk of suicide and it also constitutes a risk factor for recurrent major depressive disorder. Major depressive disorder with psychotic features responds better to treatment with a combination of an antipsychotic medication and an antidepressant medication than to treatment with either component alone. Lithium augmentation is helpful in some patients who have not responded to combined antidepressantantipsychotic medication treatment. ECT is highly effective in major depressive disorder with psychotic features and may be considered a first-line treatment for this disorder.
3. Catatonic features At times catatonic symptoms may be the presenting symptoms may be life-threatening requiring urgent ECT. Immediate relief may often be obtained by the intravenous administration of benzodiazepines such as lorazepam. For patients who show some relief, continued oral administration of lorazepam may be helpful. Concurrent antidepressant medication treatments should be considered. When relief is not immediately obtained by administering benzodiazepines, the urgent provision of ECT should be considered. The efficacy of ECT, usually apparent after a few treatments, is well documented. After the catatonic manifestations are relieved, treatment
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may be continued with antidepressant medications, lithium, antipsychotics, or a combination of these compounds. 4. Alcohol or substance abuse or dependence Because of the frequent comorbidity of depressive disorders and alcohol or other substance abuse, the psychiatrist should make every effort to obtain a detailed history of the patient's substance use. If there is suspicion that there is a problem in this area, the clinician should consider questioning collaterals for confirmation. If the patient is found to have a substance use disorder, a program to secure abstinence should be regarded as a principal priority in the treatment. A patient suffering from major depressive disorder with comorbid substance dependence is more likely to require hospitalization, more likely to attempt suicide, and less likely to comply with treatment than is a patient with major depressive disorder of similar severity not complicated by this factor. Concurrent drug abuse, especially with stimulant drugs, predisposes the patient to toxic interactions with MAOIs, although there have been few reports of such events. Benzodiazepines and other sedative-hypnotics carry the potential for abuse or dependence and should be used cautiously except as part of a detoxification regimen. Benzodiazepines have also been reported to contribute to major depressive disorder symptoms. Hepatic dysfunction and hepatic enzyme induction frequently complicate pharmacotherapy of patients with alcoholism and other substance abuse; these conditions may require careful monitoring of blood levels (if available), therapeutic effects, and side effects to avoid either psychotropic medication intoxication or inadequate treatment. 5. Comorbid panic or other anxiety disorder Anxiety symptoms/disorder often complicates the picture of depression in elderly. In major depressive disorder with comorbid anxiety or panic disorder, both the major depressive disorder symptoms and anxiety symptoms have been shown to respond to antidepressant medication treatment. Tricyclic antidepressant medications and SSRIs may initially worsen rather than alleviate anxiety and panic symptoms; these medications should therefore be introduced at a low dose and slowly increased when used to treat such patients. Alprazolam may sometimes be used with benefit in conjunction with antidepressant medications; in general, benzodiazepines should not be used as the primary pharmacologic agent for patients with major depressive disorder and anxiety symptoms, especially patients with more severe forms of major depressive disorder. 6. Major depressive disorder-related cognitive dysfunction (pseudodementia) Major depressive disorder is routinely accompanied by signs and symptoms of cognitive inefficiency. Some patients have both major depressive disorder and dementia, while others have major depressive disorder that causes cognitive impairment (i.e.. pseudodementia). In the latter case, the treatment of the major depressive disorder should reverse the signs and symptoms of cognitive dystunction. Many patients complain that their thoughts are slowed and their capacity to process information is reduced; they also display diminished attention to their self-care and to their environment.Transient cognitive impairments, especially involving attention, concentration, and memory storage and retrieval, are demonstrable through neuropsychological testing. Major depressive disorder-related cognitive dysfunction is a reversible condition that resolves with
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treatment of the underlying major depressive disorder. Several clinical features help differentiate major depressive disorder pseudodementia from true dementia. When performing cognitive tasks, pseudodemented patients generally exert relatively less effort but report more incapacity than do demented patients. The latter group, especially in more advanced stages, typically neither recognizes nor complains of their cognitive failures, since insight is impaired; in comparison, pseudodemented patients characteristically complain bitterly that they cannot think or cannot remember. Major depressive disorder pseudodementia lacks the signs of cortical dysfunction (i.e., aphasia, apraxia, and agnosia) encountered in degenerative dementia, such as Alzheimer's disease. It is vital that individuals with major depressive disorder-related cognitive disturbance not be misdiagnosed and thereby denied vigorous antidepressant medication treatment or ECT. Demographic & psychosocial variables requiring attention 1.
Major psychosocial stressors In elderly, depression often follows an adverse life event, like loss of an important human relationship or life role. Major depressive disorder episodes following life stresses are no less likely than other depressive episodes to either require or benefit from antidepressant medication treatment. Nonetheless, attention to the relationship of both prior and concurrent life events to the onset, exacerbation, or maintenance of depressive symptoms is an important aspect of the overall treatment approach. A close relationship between a life stressor and major depressive disorder suggests the potential utility of a psychotherapeutic intervention coupled, as indicated, with somatic treatment.
2.
Bereavement Bereavement is a particularly severe stressor and is commonly accompanied by the signs and symptoms of major depressive disorder. Historically, such depressive manifestations have been regarded as normative, and presentations otherwise diagnosable as major depressive disorder are therefore diagnosed in DSM-IV as uncomplicated bereavement when they begin within the first 3 months of the loss. Antidepressant medications or psychotherapy should be used when the reaction to a loss is particularly prolonged and psychopathology and functional impairment persist.
3.
Family distress The recognition of a problem in the family setting is important in that such a situation constitutes an ongoing stressor that may hamper the patient's response to treatment. Ambivalent, abusive, rejecting, or highly dependent family relationships may particularly predispose an individual to major depressive disorder. Such families should be evaluated for family therapy, which may be used in conjunction with individual and pharmacologic therapies. Even for instances in which there is no apparent family dysfunction, it is important to provide the family with education about the nature of the illness and to enlist the family's support and cooperation.
4. Cultural facto: i Specific cultural variables may hamper the accurate assessment of major depressive disorder
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symptoms. An appreciation by the therapist of cultural variables is critical in the accurate diagnosis of major depressive disorder and in the selection and conduct of psychotherapy and pharmacotherapy. 5.
Family history The presence of a positive family history of recurrent major depressive disorder increases the chances that the patient's own illness will be recurrent and that the patient will not fully recover between episodes. Those patients who improve completely also may require prophylaxis.
Treatment implications of concurrent general medical disorders As discussed earlier, there are very few studies done in medically ill elderly depressed subjects. Hence, most of the description given below is from the data on young adults, but most of the recommendations can be generalized to elderly. It is often recommended that the dose of antidepressants should be half compared to non-medically ill subjects and the same rule should be followed for elderly too (effectively one forth the dose of young adults). Cardiac disease: The presence of specific cardiac conditions complicates or contraindicates certain forms of antidepressant medication therapy, notably use of tricyclic agents; the cardiac history should therefore be carefully explored before the initiation of medication treatment. Although tricyclic antidepressants have been used effectively to treat major depressive disorder in patients with some forms of ischemic heart disease), clinicians should take particular care in using tricyclics for patients with a history of ventricular arrhythmia, subclinical sinus node dysfunction, conduction defects (including asymptomatic conduction defects), prolonged QT intervals, or a recent history of myocardial infarction. SSRIs, bupropion, and ECT appear to be safer for patients with preexisting cardiac disease, although the latter may require consultation with a specialist and treatment modification before use. However, there are also reports which suggest that SSRIs can also lead to arrhythmia. MAOIs do not adversely affect cardiac conduction, rhythm, or contraction but may induce orthostatic hypotension and also run the risk of interacting adversely with other medications that may be taken by such patients. There is anecdotal evidence that trazodone may induce ventricular arrhythmias, but the agent should be avoided in elderly because of orthostatic blood pressure decrements. A depressed patient with a history of any cardiac problem should be monitored for the emergence of cardiac symptoms, ECG changes, or orthostatic blood pressure decrements. Consultation with the patient's cardiologist before and during antidepressant medication treatment may be advisable and is especially advisable during any treatment for a patient who has recently had a myocardial infarction. Hypertension: Antihypertensive agents and tricyclic antidepressant medications may interact to either intensify or counteract the effect of the antihypertensive therapy. The action of antihypertensive agents that block alpha receptors (e.g., prazosin) may be intensified by antidepressant medications that block these same receptors, notably the tricyclic antidepressants and trazodone. Tricyclic antidepressants may antagonize the therapeutic actions of guanethidine, clonidine, or a-methyldopa. Antihypertensive, like diuretics which mainly act on kidney, may precipitate SIADH, when given along with SSRIs. Concurrent antihypertensive treatment, especially with diuretics, increases the likelihood that tricyclic antidepressants, trazodone, or MAOIs will induce symptomatic orthostatic hypotension. a Blockers, especially propranolol, may be a cause of major depressive disorder in some patients;
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individuals who have become depressed after initiation of treatment with one of these medications should be changed to another antihypertensive regimen. Dose-dependent elevations in blood pressure with venlafaxine are usually mild, although more severe elevations have been observed, making this agent less preferable in patients with hypertension. Diabetes mellitus: Selective serotonin reuptake inhibitors may reduce serum glucose by up to 30% and cause appetite suppression, resulting in weight loss. Fluoxetine should be avoided, owing to its increased potential for hypoglycaemia, particularly in non-insulin dependent diabetes. Its side-effects of tremor, nausea, sweating and anxiety may also be misinterpreted as due to hypoglycaemia389. If fluoxetine is prescribed, serum glucose should be monitored regularly. TCAs are more likely to impair diabetic control as they increase serum glucose levels by up to 150%, increase appetite (particularly carbohydrate craving) and reduce the metabolic rate. However, they are generally considered safe unless the diabetes is very poorly controlled or is associated with significant cardiac or renal disease. Antidepressants such as amitriptyline, imipramine and citalopram are also used to treat painful diabetic neuropathy. Among the mood stabilisers, lithium can be used safely in patients without renal disease. Sodium valproate may give false positive urine tests (for glucose) in patients with diabetes. Asthma: Antidepressant medications except MAOI may be used for patients with asthma without fear of interaction. Dementia: Treatment of major depressive disorder in the cognitively impaired patient requires the involvement of clinicians in the patient's pharmacotherapy, supervision, and monitoring. Individuals with dementia are particularly susceptible to the toxic effects of muscarinic blockade on memory and attention. Therefore, individuals suffering from dementia generally do best when given antidepressant medications with the lowest possible degree of anticholinergic effect, e.g., bupropion, fluoxetine, sertraline, and, of the tricyclic agents, desipramine or nortriptyline. Among SSRIs, paroxetine should be avoided. Alternatively, some patients do well given stimulants in small doses. ECT is also effective in major depressive disorder superimposed on dementia, and it should be used if medications are contraindicated, not tolerated, or if immediate resolution of the major depressive disorder episode is medically indicated (such as when it interferes with the patient's acceptance of food). Clinicians should be aware that a transient worsening of the patient's cognitive status may occur in such cases. Glaucoma: Most common type of glaucoma in elderly is acute close angle glaucoma. Antidepressants that cause or exacerbate acute close angle glaucoma include medications with anticholinergics, seratonergic or adrenergic properties. The tricyclic antidepressants have the greatest anticholinergic properties, they dilate the pupil through their effect on the iris sphinter muscle thereby causing relative pupillary block which is a trigger for an attack of acute close angle glaucoma especially in predisposed eyes. Benzodiazepines (Diazepam) have mild anticholinergics properties. SSRIs and SNRIs by v, ^ e of their action on serotonin receptor can also cause mydriasis and thereby can produce papillary block. Antidepressants lacking anticholinergic and seratonergic activity (bupropion) should be used. Obstructive uropathy: Prostatism and other forms of bladder outlet obstruction are relative contraindications to the use of antidepressant medication compounds with antimuscarinic effects. Benzodiazepines, trazodone, and MAOIs may also retard bladder emptying. The antidepressant medications with the least propensity to do this are SSRIs, bupropion, and desipramine. Parkinson's disease: Amoxapine, an antidepressant medication with dopamine-receptor blocking
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properties, should be avoided for patients who have Parkinson's disease. Lithium may in some instances induce or exacerbate parkinsonian symptoms. Bupropion, in contrast, exerts a beneficial effect on the symptoms of Parkinson's disease in some patients but may also induce psychotic symptoms, perhaps because of its agonistic action in the dopaminergic system. MAOIs (other than selegiline, also known as L-deprenyl, a selective type B MAOI is recommended in the treatment of Parkinson's disease) may adversely interact with L-dopa products. Selegiline loses its specificity for MAO-B in doses greater than 10 mg/day and may induce serotonin syndrome when given in higher doses in conjunction with serotonin-enhancing antidepressant medications. There is no evidence favoring any particular antidepressant medication from the standpoint of therapeutic efficacy in patients with Parkinson's disease complicated by major depressive disorder. The theoretical benefits of the antimuscarinic effects of some of the tricyclic agents in the treatment of patients with major depressive disorder with Parkinson's disease are offset by the memory impairment that may result. ECT exerts a transient beneficial effect on the symptoms of idiopathic Parkinson's disease in many patients. Malignancy: The prevalence rates of depression in patients with malignancy vary, because of lack of standardization of methodology and diagnostic criteria. A major difficulty in study of depression in patients with cancer has been the difficulty in distinguishing the depressive symptoms that are associated with syndromal depression from the symptoms that are caused by the patient's illness and/or treatment. Risks factors found to be associated with the development of depression are advanced disease, pain, tumor site, social factors, psychological factors, psychiatric morbidity, and treatment related factors. The direction of association between pain and depression i.e. whether depression increases the sensitivity to pain or whether pain plays on etiological role in depression is unclear. Relatively higher prevalence of depression was found in patients with pancreatic (50%), oropharyngeal (22-40%) and breast cancer patients (18-36%) in some studies390391. Para-neoplastic syndromes particularly which lead to hypothyroidism, hypercortisolism etc. are also of importance in development of depression392. Various social factors like social isolation, recent losses, and socioeconomic pressures have been reported to have a causative role in depression in cancer patients. Depression can also be a result of direct effect of drugs used to treat cancers or systemic complication of treatment393. In treatment of depression in subjects with malignancy, SSRI are considered to be the first line drugs. The advantage of SSRI is that they can act as effective adjunct analgesic drugs, especially in neuropathic pain. Disadvantages of SSRI are drug-drug interaction with drugs that are metabolized by CYP450/3A4 (e.g. cylophosphamide, doxorubicin). Fluoxetine, should be used with caution especially is patients with hepatic insufficiency, since it has a long half-life. TCAs are also good adjunct analgesics. But the disadvantages with TCAs are anticholinergic side effects and orthostatic hypotension. They can also worsen their side effects of drugs like opioids (e.g. constpation and dry mouth) which are often needed for pain control. Psychostimulants, with their rapid onset of action have some advantages for depressed cancer patients in the sense of promoting a sense of well being, decreasing fatigue, stimulating appetite, potentiating the analgesic effect of opioids and decreasing opioid induced sedation. The goal of psychological treatment in depressed patients with cancer is to reduce emotional distress, improve morale, coping ability, self-esteem and sense of control. Various treatment ranging from crisis intervention to short term dynamic therapy have been tried. Improved social support provided by family, friends, community and religious groups can be crucial. It may also be important to decrease family conflicts, and to identify family members who may be in need of psychosocial help394.
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Drug induced depression: When new or worsening symptoms of depression occur in a patient who is receiving medications, the clinician should review all medication changes occurring before the emergence of depressive symptoms and evaluate whether any of the new medications may be responsible for the observed symptoms. Medications potentially associated with the emergence of symptoms of dementia or delirium (eg, anticholinergic medications) should also be identified, as these conditions may at times present similarly to depression. If medication induced depression is suspected, the suspect drug should be discontinued if possible and replaced with another agent less likely to induce depression. When this is not possible or when discontinuation does not result in remission of the depressive symptoms, pharmacotherapy for the depression should be considered. Although there are relatively few data on the efficacy of antidepressant pharmacotherapy for medication induced depression, this approach has been shown to be successful in the treatment of depressive symptoms induced by use of interferon. Liver disease: Liver impairment affects basic elements of medication pharmacokinetics, from absorption to metabolism, distribution to elimination, changing drug levels, duration of action, and efficacy. Most antidepressants are highly protein-bound—except, venlafaxine, and methylphenidate. In liver failure, a reduction in albumin and alpha 1-acid-glycoprotein production, along with altered protein-binding, leads to higher levels of free pharmacologically- active drug. This is offset by a compensatory increase in the rate of hepatic metabolism, and this is especially important for drugs with low intrinsic clearance. Most antidepressants are highly lipid-soluble and require hepatic metabolism (biotransformation into more polar compounds) to allow them to be cleared from the body in urine or bile. Antidepressants can also be divided into two major categories of clearance, determined by their enzyme affinity. Flow-limited drugs have high hepatic extraction, and their hepatic clearance is dependent on the rate of delivery of the drug to the liver. For example, tricyclic antidepressants undergo significant firstpass metabolism of greater than 50% after oral administration. Drugs with low hepatic-enzyme affinity (e.g., paroxetine) are metabolized more slowly, as enzyme saturation is trie rate limiting step. The severity of impairment rather than the underlying aetiology is the most important factor to consider in prescribing for this group. Renal function may also be affected. As the risk of drug toxicity increases with disease severity, lower starting and total doses of medication are recommended {starting dose -about one forth that of adults). Citalopram in the lower dose range and fluoxetine at half the usual dose in elderly, or given on alternate days, will have less sedative effects. Sertraline should be avoided. The sedative and constipating side-effects of the TCAs may precipitate or unmask subclinical hepatic encephalopathy. Venlafaxine, nefazodone, mirtazapine and reboxetine should all be started at a low dose with cautious titration. Monoamine oxidase inhibitors (MAOIs) are hepatotoxic and may precipitate coma. If essential, the starting dose should be very low, with moclobemide being the safest option. As lithium undergoes minimal hepatic metabolism, it is itie mood stabiliser of choice in liver disease. Renal disease: In this group of patients, TCAs are probably safer than SSRIs. As with hepatic disease, the degree of renal impairment rather than the cause is most important. Renal impairment may be present in the elderly without a raised creatinine level. TCA metabolites are excreted by the kidneys, hence accumulation may occur. Of the SSRIs, sertraline is not recommended by its manufacturers in renal failure. Fluoxetine, citalopram and paroxetine should be started at very low dose in patients with a glomerulofiltration rate of at least >10 ml/min. Carbamazepine and valproate are the preferred mood stabilisers in renal failure. Lithium should only be prescribed if absolutely (124)
necessary, at low doses, on alternate days, with frequent checking of serum levels. Perioperative period: At times psychiatrists, dealing with patients with medical comorbidities are asked to give opinion about continuation and discontinuation of psychotropics during the perioperative period. Till recently there were no specific guidelines for the same, and the general principle was that the clinicians should weigh the pros and cons of continuing and discontinuing a particular medication. Recently Hyuse et al395 proposed guidelines for use of psychotropic agents during the perioperative period. Tricyclic antidepressants can not only lead to arrhythmias but can also interact with the anesthetic drugs regulating the cardiovascular system. Therefore, TCAs should preferably be stooped prior to surgery. Because abrupt discontinuation can cau'se'serious withdrawal symptoms, the drugs should be gradually discontinued over 2 weeks before surgery. When, postoperatively, the patient is hemodynamically stable, is able and allowed to drirtff-ur.ti is not on new, potentially interfering drugs, the medication should be restarted gradually. SSRIs can interact with pethidine, pentazocine, and dextromethorphan, at the pharmacodynamic levels and lead to serotonin syndrome, therefore such drugs should be avoided during the perioperative period. Interactions with existing physical illness and the related drug regimens should be taken into account. Discontinuation can cause withdrawal symptoms, specifically in the short-acting SSRIs. Huyse et al395 propose that SSRI should not be discontinued in order to prevent anesthetic interactions, except when the SSRI is used in combination with aspirin or an NSAID and when the SSRI is used in patients over 80 years of age. In these patients, the balance of risks of withdrawal and bleeding should be discussed with patients. As with SSRIs, the risk of serotonin syndrome also prevails for use of MAOIs and drugs like pethidine, pentazocine, and dextromethorphan should be avoided. However MAOI can contribute to hemodynamic instability and hence it is recommended to discontinue MAOI during perioperative period. Whon discontinued, they can be restarted when the patient is hemodynamically stable, is able and allowed to drink, and is not on new, potentially interacting drugs. One strategy to discontinue irreversible MAOIs is to change, in the weeks before surgery, to a reversible MAOI. The reversible MAOI moclobemide only needs to be discontinued for 24 hours to restore the depleted neurotransmitters. It can be restarted as soon as the patient is hemodynamically stable and is able and allowed to drink. However, patients have a serious risk of withdrawal, psychiatric relapse, or recurrence. The available evidence and literature for the risk during the perioperative period for other antidepressants is poor. Lithium can contribute to hemodynamic instabilities, interfere with sodium and potassium metabolism, and the renal excretion of lithium can be reduced in presence of renal complications. The physical risk of intoxication, with its detrimental and fatal risks for the CNS, is unacceptable. Therefore, lithium discontinuation is recommended. Lithium can be stopped at once because no withdrawal symptoms occur. Taking a half-life of 24 to 36 hours into account, Hyuse et al396 proposed to discontinue lithium 72 hours before surgery. When postoperative, and the patient has normal ranges of potassium, sodium, and creatinine, is hemodynamically stable, and is able and allowed to drink, lithium should be restarted, with control of blood levels, within 1 week. This is most important because the psychiatric risk of recurrence or relapse is hazardous.The same drug regimen should be provided as in the preoperative period unless kidney function has declined. How can Family and Friends Help? Depression clouds how a person's thinking and feelings and fills their minds with negative thoughts. Just telling the person that "everything will be ok, don't feel sad" is usually not of much help. However,
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there are some practical things that a family can do to help the loved one3'. •
If you suspect that your loved one is depressed, encourage him or her to see a doctor for evaluation and treatment right away. The sooner treatment is started, the sooner the person will start to feel better. Just knowing that the feelings are caused by a treatable illness can help people feel better.
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If your loved one has been diagnosed with depression, the most important thing you can do is encourage him or her to stick with treatment. If one treatment doesn't help, encourage the person not to give up but to keep trying until something helps. Many people need to try several medications before they find one that works for them.
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Offer emotional support and affection. Be patient and encouraging. Listen with understanding.
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Let the person know that you believe the treatment will help and he or she will feel better soon.
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If the person talks about death and suicide, take this very seriously, and let the person's doctor know right away. If you cannot reach the doctor, take the person to the hospital emergency room or contact a clergy member. You could be saving the person's life.
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Encourage the person to participate in activities he or she used to enjoy. Invite your loved one to go with you to cultural activities, and encourage him or her to come to social gatherings of family and friends.
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If the person is irritable or says negative things, try to remember that it is the depressive illness that is causing this.
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Finally, it is important to take care of yourself and make time to do things you enjoy.
Prevention of depression in the elderly Unipolar depression is expected to become second leading cause of disability worldwide in 2020396.Hence it is very important to prevent depression. Prevention of depression will not only lead to decreased morbidity due to depression but would also probably prevent development of other illnesses, exacerbation of coexisting illnesses, excess use of health services, severe restriction of quality of life, and unnecessary suffering because of inadequate, wrong or no treatment. For prevention it is very important to recognize the risk factors. Five risk factors which have been identified include: currently suffering from depression or history of recurrent depression; conditions which commonly precipitate depression in older people, but are undertreated; presence or risk of vascular disease; functional impairment; and nutritional deficiencies397. In prospective studies, the biggest predictor of depression at follow-up is depression at baseline398. Sixty per cent of older people with prior depression have at least one late-life episode, and 40% remain chronically affected399. Chronic insomnia, pain, and incontinence commonly precipitate depression400402. Post-stroke depression is common, with prevalence estimates of 10%-64%403. Vascular disease, or even risk of vascular disease in the absence of stroke, is also a major risk factor for late-onset depression. Patients with late-onset depression are significantly more likely than younger subjects to have two or more risk factors for vascular disease404. Lack of mobility, and consequent inability to perform activities of daily living (ADL). is both a direct and an indirect predictor of depression405. Research also shows link between depression and certain metabolites, in particular deficient folate and vitamin B12 and elevated homocysteine levels406. The risk is much greater for older people because the incidence of these abnormalities increases rapidly with age407.
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Some of these factors can be modified by preventive programs, as discussed by Bird & Parslow397. Potential for primary preventive programs Increasing literacy about depression in old age: Probably the largest effect on prevalence could be made by increasing the chances, currently not high, that depressed older people will actually be treated for depression. A smaller effect could be made by increasing the chances that older people suffering conditions that often lead to depression, such as pain, primary insomnia or incontinence, receive adequate treatment. For depression, because of the alarming chronicity and relapse rates, maintenance pharmacological therapy has been advocated for people with recurring symptoms. For practitioners treating medical conditions, a more inclusive diagnostic process might be introduced, so that neurovegetative symptoms are explicitly investigated as evidence of depression rather than side effects of physical illness. The primary care physicians, who provide the bulk of consultations, and other healthcare practitioners dealing with chronic illness in older people, should be educated and trained to pickup depression and treat adequately. Groups at particular risk for depression could be targeted besides the population at large — for example, people who have lost a spouse or those acting as informal carers. Exercise: The strongest lifestyle candidate for prevention is exercise. There is excellent evidence that, for older people suffering mild to moderate depression, regular physical exercise produces alleviation of symptoms equal to the effects of antidepressant medication. Exercise has also been an important adjunct in major depression. A meta-analysis of 30 studies found an overall mean effect size of 0.7212. The long-term effects of exercise may also alleviate two important risk factors for depression: vascular disease, and physical and functional mobility or falls, with attendant risk of disability. Exercise does not have to involve major lifestyle changes; it can involve simply a walk every day, or resistance training at home. However, all studies on depression are with clinical samples, and a recent metaanalysis of controlled trials concluded that what is now. needed is "A well-designed randomized controlled trial with long-term follow-up." Nutritional supplements: A recent comprehensive review of nutritional and vascular risk factors for late-life depression concluded that, as folate and vitamin B12 are cheap, easily taken and readily correct elevated homocysteine levels, a more intensive evaluation df their effects is required in a large sample of older patients, and, prospectively, in people at risk of late-life depression404. Given the consistent associations between these metabolites and both depression and vascular disease (a major risk factor for late-life depression), this is an extremely plausible preventive measure. Nutrition supplementation is already occurring in several countries, including the US, where folate is added to grains. The hope is for reduction in prevalence of a number of disorders, including cardiovascular disease. Role of Secondary Depression This is aimed at reducing the risk of a recurrence or a relapse of depression. This will involve timely and optimum treatment in the acute phase, and appropriate continuation treatment and prophylaxis. Without planned after care, relapses and recurrences often go undetected. There is some evidence of the efficacy of maintenance ECT. Role of Tertiary Prevention
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