Focus on CME at the University of Western Ontario

Recognizing & Title Treating Major in All the

Depressive Disorders Wrong Places

John Jordan, MD, MCISc, CCFP, FCFP

Case Mary is a 42-year-old teacher with a history of depression, decreased energy and decreased concentration for the past four months. She describes worrying about her students, her family and her home renovations. Mary has trouble sleeping and notes recent friction with colleagues at work. She describes muscle tension and a feeling of being “keyed up” and restless most of the time. Questions: What further information would you like before diagnosing this patient? Should she be offered an antidepressant? What would you want to discuss with her before prescribing treatment? How would you monitor response to treatment? After starting Mary on an antidepressant, she returns to see you for regular follow-up appointments. A few months later, she reports a return of depression, decreased interest in things, concentration difficulties and loss of appetite. She has also noticed some increased anxiety and tension. There are no triggers you can identify preceding the symptom onset. Question:

What would you do now?

he impact of depressive illness on our society is great. One in every six people will develop an episode of major depression over the course of their lifetime.1 Major depressive disorder is more common in women, with a lifetime risk of 10% to 25% being reported. For men, the lifetime risk is reported to be between 5% and 10%.2 The prevalence of depression is not related to education, income, mar-

T

ital status or ethnic background. An estimated three million Canadians are suffering from depression.3 Of those that meet the criteria for major depression, only about one-quarter have been diagnosed with depression. Many people who are depressed don’t reach out for help and, therefore, don’t engage the health-care system. Many of those that do seek care for their discomfort or distress are not recogThe Canadian Journal of CME / November 2002 73

Antidepressants nized as being depressed. Physical symptoms may become the focus of attention and result in missed or delayed diagnoses. In recent years, depression has come to be recognized as a chronic condition. Only 20% of patients suffering an episode of major depression are fully recovered at 15-year followup.4,5 Most people who develop a major depressive disorder probably have some vulnerability or predilection to its occurrence. There is usually a trigger that precipitates a person’s first episode of major depression, however, this trigger is not always recognized by the patient or the treating physician.

Assessment and Diagnosis A diagnosis of major depression requires the subjective feeling of sadness present on most days, for most of the day, for greater than two weeks or a lack of interest in doing things over a similar period of time. Also required to make the diagnosis are at least four other symptoms commensurate with the diagnosis.2 Included in the extended symptom inventory for depression that family physicians need to address if the patient presents with loss of interest or depressed mood include: • Any change in sleep pattern; • Loss of energy; • Change in appetite;

Dr. Jordan is an associate professor, department of family medicine, University of Waterloo, and acting chief of family medicine, London Health Sciences Centre, London, Ontario.

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• Difficulty concentrating; • Feelings of worthlessness; and • Any suicidal thoughts. The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) indicates the accepted criteria for diagnosing major depression.6 There are also several excellent evaluative tools that can assist the physician in diagnosing and quantifying the severity of major depressive disorders.7-11 Assessment tools for depression may be subjective (depending on the patient completing a questionnaire), or objective (requiring someone to administer the test and score the patient based on the questions posed). Both types of tests have their advantages. Table 1 lists the most popular, validated and reliable assessment tools available to care providers. Occult depression is a subtype seen in the family physician’s office that presents with nonspecific or somatic complaints. Depressed mood is not recognized as a prominent feature by the patient or their attending physician when dealing with occult depression. A patient who is unusually grumpy, angry, anxious or negative should rouse the family physician’s suspicion of a possible underlying depressive disorder. Further probing to identify signs of functional impairment in school or at work should also be looked for. A degree of disinterest in usual activities and hobbies may be uncovered. Sleep disturbance is also usually part of the presentation. Giving the patient a diagnosis of depression in this setting requires some tact, as the patient with occult depression typically won’t initially accept or believe the diagnosis. He or she may become angry if they feel their somatic symptoms have been discounted. How the suspected diagnosis is framed and presented to the patient is critical if the family physician is to find common ground and obtain the patient’s agreement to treatment. This is not usually achieved on the patient’s first visit, but

Antidepressants once other explanations are ruled out and trust in the doctor-patient relationship is established, the patient will usually agree to consider a trial of antidepressant treatment. Every depressed patient should be evaluated for suicide risk. To do so effectively, one has to first establish a degree of rapport with the patient. This is usually achieved through empathic listening in order to better understand the patient’s perspective. Once a degree of trust has been established, the physician should seek to obtain more information about the patient’s thought processes. Important determinations here are the patient’s degree of hopelessness, desires to die, plans being considered and, if so, how lethal the plans are. If the patient is contemplating suicide, an assessment of the availability of the lethal means should be made. Prior attempts, family history of suicide and use of alcohol or other substances of abuse all increase the degree of risk present.2 The presence and degree of psychosocial stressors is also an important factor to consider. In the differential diagnosis of depression, bipolar spectrum disorder warrants special consideration because it can easily be mistaken for major depressive disorder. The presence of periods of energetic activity or mood lability should rouse suspicion. A seasonal variation in mood is common with bipolar illness and there is often a positive family history.13 Remember, anxiety disorders can be confused for, or associated with, major depressive disorder in as many as 30% of cases.14 Anxiety disorders and depressive disorders share many common features, including feelings of worry, guilt, restlessness, nervousness, impaired concentration, insomnia and fatigue. Loss of a loved one is a crisis point in a person’s life and may trigger a depressive disorder in someone who is prone or vulnerable to developing 76 The Canadian Journal of CME / November 2002

Table I

The Most Popular Assessment Tools For Major Depression Subjective Tools Beck Depression Inventory Burns Depression Checklist MINI Patient Health Survey Geriatric Depression Scale Objective Tools Hamilton Depression Rating Scale HAMD-7 (abbreviated Hamilton Depression Rating Scale) Clinical Global Assessment Scale

depression. Bereavement is a natural process of coming to terms with a significant loss. It shares many of the symptoms of depression, including a pervasive sadness, difficulty sleeping, emotional pain and disengagement. It is distinguished from depressive disorders by less worry about past actions, less slowed thinking and less suicidal thinking. It often takes a year or longer for grief reactions to resolve.15 When the grieving individual develops more severe and persisting symptoms of guilt, agitation or delusions, the physician should suspect that a major depressive disorder might have developed. This is sometimes referred to as a pathologic grief reaction.

Initiating Treatment A selective serotonin reuptake inhibitor (SSRI) is the type of antidepressant most commonly prescribed first by family physicians for major depressive illness. Fluoxetine was the first com-

Antidepressants

Table 2

Types of Antidepressants Class

Examples

SSRIs

Fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram

SNRI

Venlafaxine

NDM

Bupropion

NaSSA

Mirtazapine

RIMA

Moclobemide

SARI

Nefazodone

TCAs

Amitryptiline, clomipramine, desipramine

SSRI = selective serotonin reuptake inhibitor SNRI = serotonin and norepinephrine reuptake inhibitor NDM = norepinephrine and dopamine modulator NaSSA = noradrenaline and selective serotonin antidepressant RIMA = Reversible monoamine oxidase inhibitor antidepressant SARI = Serotonin-2 antagonists/reuptake inhibitors TCA = Tricyclic antidepressant

mercially available SSRI. Now there are four others on the market, including paroxetine, sertraline, fluvoxamine and citalopram. It takes four to six weeks to assess the efficacy of drugs from this class. The most common short-term adverse effects of SSRIs include lightheadedness, headaches, restlessness, tremor and gastrointestinal side effects. Longterm side effects to watch for include weight gain, somnolence and sexual dysfunction. These drugs are safe in overdose. All, except fluoxetine, may be associated with a discontinuation syndrome that may consist of dizziness, nausea, paraesthesias and headaches. For this reason, they should be gradually tapered before discontinuation. Research data reveal that SSRIs achieve a full remission in only 30% of cases of major depression.16 They result in a partial response in 50% of 78 The Canadian Journal of CME / November 2002

cases and no response in 20% of patients with major depression. Other first-line choices include: venlafaxine, a serotonin and noradrenaline reuptake inhibitor (SNRI); bupropion, a norepinephrine and dopamine modulator (NDM); mirtazapine, a noradrenaline and selective serotonin antidepressant (NaSSA); and nefazodone, a serotonin-2 antagonists/reuptake inhibitor (SARI). As the medical community comes to understand more clearly the different mechanisms by which antidepressant medications work, clinicians should be able to predict which agent might be the best first choice for a particular patient. This decision should be guided by the patient’s dominant symptom concerns and side-effect profiles of the various medications available (Table 2). SSRIs, SNRIs and NaSSAs all have anxiolytic as well as antidepressant effects. Recommendations for the duration of antidepressant therapy have been extended during the past decade. Current Canadian guidelines (CANMAT 2001) recommend at least six months of treatment for first episodes of uncomplicated major depression after achieving clinical remission, and longer if there are risk factors.17 Chronic depression, recurrent episodes of depression and depression in the elderly require treatment for at least two years. Followup of patients treated with antidepressant medication should be at least every two weeks during the acute phase and monthly during the maintenance phase of treatment. The frequency of assessment will ultimately be dictated by the individual patient as well as by practice variables.

What To Do When Firstline Therapy Fails There should be some evidence of at least partial response after four weeks at a therapeutic dosage. When the patient fails to respond to the firstchoice antidepressant, the family physician should

Antidepressants first reassess the diagnosis and consider the possiSSRIs, Nefazodone Serotonin bility of other comorbidities, including drug or alcohol abuse. Consideration should also be given to the possible presence of bipolarity. If the diagVenlafaxine, Mirtazapine Serotonin + Norepinephrine nosis still appears to be correct, then treatment issues should be reviewed. This would include an exploration of adherence, side effects and possible Bupropion Norepinephrine + Dopamine drug interactions. When there appears to be a partial response, the Tricyclics Norepinephrine next logical step would be to consider an increased dosage of the same antidepressant. No further MAOIs Norepinephrine + Dopamine + improvement over the next two weeks should lead Serotonin the family physician to consider augmentation with lithium, triiodothyronine (T3) or bupropion.17 SSRI = selective serotonin reuptake inhibitor Response to the augmenting agent will be apparent MAOI = monoamine oxidase within two weeks if it is to occur. When the initial antidepressant shows no sign of Figure 1. Effects of antidepressants on brain a response by four weeks, it should be discontinued neurotransmitter levels. and a second antidepressant from the same class or from a different class should be chosen. Troubling side effects would suggest the switch should be an augmenting agent, a switch in antidepressants made to a different class. Antidepressants that act or to an addition of a second antidepressant (comby dual mechanisms or raise levels of more than bination therapy), a psychiatric consultation one neurotransmitter are thought to be more potent should be obtained. Consultation should also be (Figure 1). sought when the patient is suiciBupropion can be used as an dal, when there is severe comoraugmenting agent or as part of bidity, when hospitalization is combination antidepressant therrequired or when the diagnosis apy. It complements the action is in doubt. 18 of SSRIs quite well. Low-dose Psychotherapy also plays an desipramine (TCA) 50 mg to 100 important role in the treatment mg can also be added to an SSRI. of mild or moderately depressed WHY IS THIS Both of these combinations are patients. In the severely DUCK SMILING? relatively safe and should show depressed patient, it is usually To find out see page 94 results within two to four weeks. best held until antidepressant More aggressive combinations of drugs have reduced the intensity antidepressants should be left to of the symptoms. Before the the psychiatrist (i.e., SNRI + SSRI, SNRI + NDM, patient can take advantage of counseling, they NaSSA + SNRI, NaSSA + SSRI, NaSSA + NDM have to first achieve some degree of symptom and TCA + monoamine oxidase inhibitor [MAOI]). control. If the patient fails to respond to the addition of The four broad types of therapy include: cogThe Canadian Journal of CME / November 2002 79

Antidepressants nitive behavioral therapy, interpersonal therapy, psychoanalytic therapy and supportive psychotherapy. There is good evidence that psychotherapy, in combination with antidepressant medication, is more effective in treating depression than either used alone.19-21

Conclusion Major depressive disorder is common. It is managed in large part by the family physician. After all, there aren’t enough psychiatrists available to treat most patients who develop a depressive disorder. The majority of patients don’t achieve full remission with the first-line antidepressant medication. However, there are strategies available to family physicians for effectively managing most of their patients presenting with major depressive disorder. CME

References 1. Davidson JR, Meltzer-Brody SE: The underrecognition and undertreatment of depression: What is the breadth and depth of the problem? J Clin Psychiatry 1999; 60(Suppl. 7):4-9. 2. Canadian Network for Mood and Anxiety Treatments: Guidelines for the diagnosis and pharmacological treatment of depression. First Edition. Cameron McCleery Productions Ltd., Toronto, 1999, pp. 6-8. 3. Business and Economic Roundtable on Mental Health: The unheralded business crisis in Canada: Depression at work. Unpublished paper, 2000. 4. Kiloh LG, Andrews G, Neilson MD: The long-term outcome of depression. Br J Psychiatry 1988; 153:752-7. 5. Judd LL, Hagop SA, Maser JD, et al: A prospective 12-year study of subsyndromal depressive symptoms in unipolar major depressive disorders. Arch Gen Psychiatry 1998; 55:694-700. 6. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders. Fourth Edition. American Psychiatric Association, Washington, 1994, p. 327. 7. Beck AT, Ward CH, Mendelson M, et al: An inventory for measuring depression. Arch Gen Psychiatry 1961; 38:764-8. 8. Burns D: Feeling Good: The New Mood Therapy. Morrow, New York, 1980, pp.20-2.

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9. Sheehan DV, Lecrubier Y, Harnett-Sheehan K, et al: The validity of the Mini International Neuropsychiatric Interview (MINI) according to SCID-P and its reliability. Eur Psychiatry 1997; 12:232-41. 10. Yesavage JA: Depression in the elderly: How to recognize masked symptoms and choose appropriate therapy. Postgrad Med 1992; 91(1):256. 11. Hamilton M: A rating scale for depression. J Neurol Neurosurg Psychiatry 1960; 23:56-62. 12. McIntyre RS, Kennedy SH: Validation of an abbreviated Hamilton depression rating scale: Hamilton Rating Scale For Depression, 7-item. Poster presented at Canadian Psychiatric Association Annual Meeting, Victoria, October 2000. 13. Hirschfeld RM, Williams JB, Spitzer RL, et al: Development and validation of a screening instrument for bipolar spectrum disorder: The Mood Disorder Questionnaire. Am J Psychiatry 2000; 157:1873-5. 14. Zajecka JM, Ross JS: Management of comorbid anxiety and depression. J Clin Psychiatry 1995; 56(Suppl. 2):10-3. 15. Edwards V: Depression and Bipolar Disorders. Key Porter Books, Toronto, 2002, p. 24. 16. Ferrier IN: Treatment of major depression: Is improvement enough? J Clin Psychiatry 1999; 60 (Suppl. 6):10-4. 17. Canadian Psychiatric Association: Clinical guidelines for the treatment of depressive disorders. Can J Psychiatry 2001; 46(Suppl. 1):50-1, 96. 18. Frye MA, Ketter TA, Leverich GS, et al: The increasing use of polypharmacotherapy for refractory mood disorders: 22 years of study. J Clin Psychiatry 2000; 61(1):9-15. 19. Keller MB, McCullough JP, Klein DN, et al: A comparison of nefazodone, the cognitive behavioural-analysis system of psychotherapy, and their combination for the treatment of chronic depression. N Engl J Med 2000; 342:1462-70. 20. Frank E, Kupfer DJ, Perel JM, et al: Three-year outcomes for maintenance therapies in recurrent depression. Arch Gen Psychiatry 1990; 47:1093-9. 21. Reynolds CF, Perel JM, Frank E, et al: Three-year outcomes of maintenance nortryptiline treatment in late-life depression: A study of two fixed plasma levels. Am J Psychiatry 1999; 156:1177-81. Suggested Reading 1. Burns D: Feeling Good: The New Mood Therapy. Morrow, New York, 1980. 2. Canadian Psychiatric Association: Clinical guidelines for the treatment of depressive disorders. Can J Psychiatry 2001; 46(Suppl. 1). 3. Edwards V: Depression and Bipolar Disorders. Key Porter Books, Toronto, 2002. 4. Greenberger D, Padesky C: Mind Over Mood. Guilford Press, New York, 1995. 5. Zajecka J: Clinical Issues in Long-term treatment with antidepressants. J Clin Psychiatry 2000; 61 (Suppl. 2).