Neuromodulation Therapies for Geriatric Depression

Curr Psychiatry Rep (2015) 17: 59 DOI 10.1007/s11920-015-0592-y GERIATRIC DISORDERS (W MCDONALD, SECTION EDITOR) Neuromodulation Therapies for Geria...
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Curr Psychiatry Rep (2015) 17: 59 DOI 10.1007/s11920-015-0592-y

GERIATRIC DISORDERS (W MCDONALD, SECTION EDITOR)

Neuromodulation Therapies for Geriatric Depression Verònica Gálvez 1,2 & Kerrie-Anne Ho 1,2 & Angelo Alonzo 1,2 & Donel Martin 1,2 & Duncan George 1,2 & Colleen K. Loo 1,2,3

Published online: 22 May 2015 # Springer Science+Business Media New York 2015

Abstract Depression is frequent in old age and its prognosis is poorer than in younger populations. The use of pharmacological treatments in geriatric depression is limited by specific pharmacodynamic age-related factors that can diminish tolerability and increase the risk of drug interactions. The possibility of modulating cerebral activity using brain stimulation techniques could result in treating geriatric depression more effectively while reducing systemic side effects and medication interactions. This may subsequently improve treatment adherence and overall prognosis in the older patient. Among clinically available neuromodulatory techniques, electroconvulsive therapy (ECT) remains the gold standard for the treatment of severe depression in the elderly. Studies have proven that ECT is more effective and has a faster onset of action than antidepressants in the treatment of severe, unipolar, geriatric depression and that older age is a predictor of rapid ECT response and remission. The application of novel and more tolerable forms of ECT for geriatric depression is currently being examined. Preliminary results suggest that right unilateral ultrabrief ECT (RUL-UB ECT) is a promising intervention, with similar efficacy to brief-pulse ECT and fewer adverse cognitive effects. Overall findings in repetitive transcranial magnetic stimulation (rTMS) suggest that it is a safe intervention in geriatric depression. Higher rTMS stimulation

This article is part of the Topical Collection on Geriatric Disorders * Colleen K. Loo [email protected] 1

School of Psychiatry, University of New South Wales (UNSW), Hospital Road, 2031, Randwick, Sydney, NSW, Australia

2

Black Dog Institute, Hospital Road, 2031, Randwick, Sydney, NSW, Australia

3

Department of Psychiatry, St George Hospital, Level 2, James Laws House, Gray St, Kogarah, 2217 Sydney, NSW, Australia

intensity and more treatments may need to be given in the elderly to achieve optimal results. There is no specific data on vagus nerve stimulation in the elderly. Transcranial direct current stimulation, magnetic seizure therapy and deep brain stimulation are currently experimental, and more data from geriatric samples is needed. Keywords Geriatric . Depression . Electroconvulsive therapy (ECT) . Repetitive transcranial magnetic stimulation (rTMS) . Transcranial direct current stimulation (tDCS) . Neuromodulation

Introduction Geriatric depression has a prevalence ranging from 5.5 to 12.5 % [1] and represents a costly public health burden (approximately 50 % higher ambulatory and inpatient costs for depressed elderly compared to non-depressed elderly) [2]. Furthermore, geriatric depression is a heterogeneous and complex disorder with multiple etiologies and clinical presentations. It can be chronic, recurrent, or present for the first time in late-life [3]. It could include melancholia, psychotic depression, agitated depression, bipolar depression, vascular depression, dysthymia, late-onset depression (first episode of depression occurring after 60–65 years), poststroke depression and depression related to medical illness (e.g., neurologic and neurodegenerative conditions). It can also present as a prodrome or a symptom of cognitive decline or dementia [4]. Geriatric depression is associated with higher levels of medical morbidity, cognitive impairment and mortality, both from suicide and medical illness [5]. The course and prognosis of geriatric depression are often more complicated, with longer time to recovery, frequent residual symptoms (50 % of chronicity rates reported) and recurrences, difficulties in tolerating antidepressants and medical comorbidities that might

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limit the prescription, dosage and use in combination of psychotropics [6–8]. In addition, between 30 to 50 % of older depressed patients do not respond to one antidepressant trial of adequate dose and duration [9, 10], although definitive rates of treatment resistance are unclear in the elderly due to the paucity of evidence. These relatively poorer clinical outcomes and limitations with pharmacotherapy heighten the need to optimise electroconvulsive therapy (ECT) and develop newer brain stimulation treatments, which have the potential to modulate brain activity and which may constitute safe and efficacious treatment options for the elderly depressed in the future. The aim of this review is to critically evaluate the literature regarding geriatric depression and the efficacy and safety of established and experimental brain stimulation techniques, highlighting relevant findings in the last 3 years.

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remission rates (63.8 % after 6 weeks in the ECT group vs 33.3 % after 12 weeks in the medication group) were significantly higher for the ECT group, even though they presented with significantly greater treatment resistance (mean number of failed antidepressants in current episode, in the ECT group 2.4±1.2 vs 0.9±0.8 in the medication group). After adjustment for clinical and demographic differences between the groups, the ECT group was 8.2 times more likely to achieve remission (within 5 weeks) than the medication group. Despite the limitation that this study was based on analysis of data compiled from two different RCTs, these results present compelling findings, suggesting that ECT should be a priority treatment option for severe unipolar geriatric depression. Faster and higher remission rates also translate into less risk of relapse and chronicity in this population [25], which ultimately leads to improvement in overall prognosis, quality of life and health economic costs (e.g., reduction in hospital stays).

Electroconvulsive Therapy (ECT) ECT Use in the Elderly ECT is effective, safe and has a fast onset of action [11]. Data from a recent review of ECT studies conducted worldwide reported that one third of patients treated with ECT in Australia and New Zealand were over 65 years old, and 48– 59 % of the patients treated in the USA were over 60 [12]. Moreover, reports on rates of ECT use suggest that older adults receive ECT at a higher rate than the overall population (e.g., 99.88 per 100,000 patients vs 37.85 per 100,000) [13–15] and that in fact, the highest rates of ECT use might be among the old-old population (>75–80 years old) [14]. ECT Efficacy in the Elderly ECT plays an important role in the treatment of geriatric depression. The elderly frequently need an intervention with a rapid onset, as they can present with high depression severity (e.g., agitation, psychosis), present a greater risk of suicide [16–18], are more prone to suffer from the physical consequences of depression (e.g., dehydration, malnutrition, weight loss) [19] and respond more slowly to antidepressants [8, 20]. ECT has been shown to have superior efficacy to antidepressant medication among patients of all ages [21]. Specific efficacy data in the elderly have recently been published. Spaans et al. [22••] compared remission data from elderly in-patients (≥60 years) participating in a randomised controlled trial (RCT) comparing different medications (mean age 72.2±7.6 years, range 60–93, n=81) [23] with data from elderly in-patients in an RCT examining different forms of ECT (mean age 74.0±7.4 years, range 60–93, n=47) [24]. Speed of remission (mean time to remission for ECT group 3.1 ± 1.1 weeks vs 4.0 ± 1.0 weeks for medication) and

Individual Patient and ECT Factors: Implications for Efficacy Importantly, efficacy outcomes in ECT may be contingent on patient (e.g., demographic and clinical factors) and ECT treatment factors (e.g., type of technique used). Individual Factors: Age ECT remission rates in geriatric depression are high (50– 90 %) [26–28] and appear to be higher than in younger depressed populations. A large prospective study (n=253) comparing the efficacy of bitemporal (BT) ECT in older and younger patients found that the elderly presented higher remission rates (90 % in ≥65 years vs 75 % in ≤45 years) and identified age as a significant predictor of superior antidepressant response, after adjusting for psychosis, severity and number of prior episodes [26]. In a large RCT (n=230) by Kellner et al. [29], remission rates were 64 % for BT ECT and 55 % for right unilateral ECT (RUL) in all age groups. However, a subanalysis separating remission rates in older (≥60 years) and younger (45 years. In the active group, there was an inverse relationship between age and improvement in depressive symptoms. Patients ≥55 years had similar response as younger patients.

Age-related findings

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Open label

Double-blind RCT

Randomised, open label

Double-blind RCT

Open label

Mosimann et al. [98] (n=13)

Kozel et al. [83] (n=29)

Grunhaus et al. [102] (n=20)

Padberg et al. [77] (n=18)

Figiel et al. [81] (n=50) 60 22–89

63.5 (15.8) 22–89 46.7 (14.7) 28–76

NR

42.4 (7)d NR 42.6 (14)d NR 58.4 (15.7) ≥18

22

0

4

NR

NR

Sample ≥65 yearsb (n)

56.4 (12.7) 40–74

Mean age (SD) Age range

L, 5 sessions, 10 Hz, 110 %, 500 stimuli

L, 5 sessions, 10 Hz, 90 %, 250 stimuli L, 5 sessions, 0.3 Hz, 90 %, 250 stimuli

L, 10 sessions, 5 Hz, 100 %, 1600 stimuli L, 10 sessions, 20 Hz, 100 %, 1600 stimuli L, 20 sessions, 10 Hz, 90%c

L, 10 sessions, 20 Hz, 100 %, 1600 stimuli

TMS parametersf

NR

NR

NR

NR

21.2 (18.0)

Percentage improvement on HDRS scores (SD) in patients ≥65 yearsb

f

e

d

c

b

a

23/NR

NR

NR

NR

NR

Response / remission (%) in patients ≥65 yearsb

Only 23 % of older patients responded, compared to 56 % of younger patients.

Age was not formally tested though it appears that there was no difference between younger and older participants. Modest reduction in HDRS scores in the 0.3 Hz group only, which tended to be younger than the 10 Hz group.

Significant negative correlation between antidepressant response and distance between the coil and the cortex. Responders were significantly younger than non-responders.

Age-related findings

Percentage (%) refers to stimulus intensity (relative to resting motor cortical threshold) and hertz (Hz) refers to stimulus frequency. R right, L left. The total number of stimuli per session is given

In the rTMS group only. Age breakdown of placebo arm not reported

Mean age for active rTMS group, as overall mean average not reported

Specific number of stimuli not reported

Unless other age range specified

Unpublished

RCT randomised-controlled trial, DLPFC dorsolateral prefrontal cortex, SD standard deviation, NR not reported

Study type

Authors

Table 1 (continued)

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Double-blind RCT

Manes et al. [106] (n=20)

L, 5 sessions, 20 Hz, 80 %, 800 stimuli

c

b

a

0/0

6.5

39.7

38

20.6

31.6

42.4

30/20

30/10

45.5/NR

30/10

39.4/27.3

33.3/13.3

14.3/0

26.7

33.1

22.6/9.7

58.5/29.2

Response/remission (%)

26.1

48.6

Percentage improvement on HDRS scores (SD)

Active treatment was more effective than sham in treating post-stroke depression. This was not influenced by age. Difference between active and sham group not statistically significant. No significant differences between responders and non-responders in age.

Five patients with vascular depression showed clinically significant but not statistically significant antidepressant response.

Statistically significant reduction in depression scores across all patients.

Increasing the number of treatments resulted in more patients with vascular depression responding. Older participants (≥65 years) benefited more from additional sessions than younger participants (10 sessions and >100 % of motor threshold, MT), which may explain the divergent findings with other studies [79, 81]. A study of predictors of rTMS response by Brakemeier et al. [87] including 70 patients (mean age 49.50 years, range 26–86) did not find age to be a predictor of response. More recent evidence also supports the findings that age does not exert an influence on rTMS efficacy. A meta-analysis of 31 RCTs on the efficacy of rTMS [88] and a recent meta-analysis of 40 studies [89•] found that age was not a predictor of response to rTMS, though age ranges were not reported and the proportion of geriatric patients represented in both samples is unclear. rTMS Efficacy: Specific Studies in the Elderly A small number of open-label studies have specifically assessed rTMS efficacy in geriatric samples, reporting response rates from 20 to 50 % (see Table 2). A recent openlabel study by Hizli Sayaer et al. [90•] administering left highfrequency rTMS (25 Hz, 100 % MT, 18 sessions) and including 65 treatment-resistant geriatric patients (≥2 antidepressants failed, 60–83 years) found significant decreases in depression scores, with a 58.46 % response rate and 19 patients meeting remission criteria. In a sequential RCT of rTMS in two cohorts of patients with vascular depression (≥50 years), Jorge et al. [91] examined the effect of 10 or 15 sessions of rTMS (10 Hz, 110 % of MT). Within this study, the first cohort received 10 treatments and showed a 33.1 % improvement in

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Hamilton Depression Rating Scale-17 (HAMD-17) scores. The second cohort was given 15 treatments at the same stimulation parameters, with improvement in HAMD-17 scores of 42.4 %. Further analysis showed a significant interaction effect with age such that older patients (≥65 years) showed greater improvement than the younger patients when the number of sessions was increased. In an RCT of rTMS for poststroke depression (mean age 63.1±8.1 years, in the active condition), Jorge et al. [92] found that there was a 38 % improvement in depression severity, though age was not correlated with efficacy in this sample. However, two open-label studies (age range 58–89 years) reported more modest outcomes, with a 31.6 % reduction in depression severity and 30 % rate of response [93] and a 24.7 % reduction in depression severity and 18.4 % response rate [94]. It should be noted, however, that the stimulation parameters used in these studies would now be considered suboptimal (10 sessions, 100 % MT). Another open-label study utilising similar rTMS parameters (10 sessions, 100 % MT) and including geriatric patients with vascular depression (56–77 years) likewise found a modest magnitude of improvement (20.6 %) [95]. Individual Patient and rTMS Factors—Implications for Efficacy Individual Factors: Structural Brain Alterations Structural particularities of older brains, such as generalised cortical atrophy and pre-frontal atrophy [96], might explain the lower rates of response sometimes reported in geriatric patients. Cortical atrophy results in a greater distance between the skull and the cortex, diminishing the possibility of an effective stimulation as the strength of the magnetic field decreases exponentially with distance [97]. Indeed, Mosimann et al. [98] found a negative correlation between antidepressant efficacy and distance between the rTMS coil and the cerebral cortex. While Kozel et al. [83] did not find an association, they reported a maximum age and coil-distance threshold for response. This was such that responders tended to be 50 years)

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may respond well to a combination of tDCS and cognitive training although it is uncertain whether this applies to the geriatric population due to insufficient numbers (n = 3). Furthermore, tDCS may have positive effects on cognition independent of its effects on mood [119–122]. Thus, its potential antidepressant and cognitive enhancing effects and the absence of major side effects make tDCS a promising treatment option for depression in geriatric populations.

Other Neuromodulatory Techniques (Vagus Nerve Stimulation (VNS), Deep Brain Stimulation (DBS), Magnetic Seizure Therapy (MST)) Other neuromodulatory techniques involving invasive (VNS, DBS) as well as non-invasive (MST) techniques may have potential efficacy in the geriatric population although no study to date has specifically examined a depressed geriatric sample. VNS has been approved as an adjunctive treatment for treatment-resistant depression in the USA, although there is no specific data on the depressed elderly. Results from studies investigating the efficacy of VNS in mixed age samples remain inconclusive possibly due to the absence of consensus as to the optimum stimulation parameters. Notably though, the first randomised study to systematically compare response to differing doses of VNS has found that while there was significant improvement regardless of electrical dose strength, there was significantly greater longevity of response with high and medium doses [123]. DBS is still an experimental technique for the treatment of depression. A positive response to DBS with electrodes placed in the nucleus accumbens or subcallosal cingulate cortex has been reported in two geriatric cases with treatment-resistant depression [124, 125]. Moreover, in three patients reported by Schlaepfer et al. [125], the geriatric patient showed the strongest correlation between stimulation strength and depression rating scores. Results from mixed age open-label treatments are encouraging, with response rates ranging from approximately 40 % to as high as 92 % and remission rates from 35 to 60 % [126]. However, there are few controlled studies [125, 127, 128], and efficacy data is generally constrained by small sample sizes. MST is also an experimental technique in which a seizure is induced using a magnetic field. In mixed aged samples, MST has shown similar efficacy [129] but fewer cognitive side effects [130] compared to RUL brief pulse ECT. Patients who received MST reached full orientation more quickly and performed better on tests of attention and non-verbal retrograde amnesia [130]. However, further research is needed to investigate its efficacy under blinded, sham-controlled conditions.

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Recommendations and Conclusions ECT remains an essential treatment for geriatric depression and should be considered as a first-line option for severe or psychotic depression in the elderly (see Fig. 1). The riskbenefit ratio between efficacy and cognitive side effects is particularly important in this population, and ECT technique should be tailored accordingly. Novel forms of ECT need to be specifically tested in the elderly (RUL-UB, BF placements) to assess their efficacy and tolerability. rTMS appears to be well tolerated in the elderly and has been shown to have moderate efficacy in treating non-psychotic geriatric depression. Higher intensities and greater number of treatments might need to be considered in the elderly to achieve optimal antidepressant responses. Of the experimental brain stimulation techniques, tDCS has the most data for geriatric depression. Evidence to date is limited but suggests comparable efficacy and side effects to the general adult population. Acknowledgments The authors would like to thank Drs. Padberg, Palm, Brunoni, Ferrucci and Priori for kindly providing data on geriatric participants in their samples.

Compliance with Ethics Guidelines Conflict of Interest Verònica Gálvez, Kerrie-Anne Ho, Angelo Alonzo, Donel Martin and Duncan George declare that they have no conflict of interest. Colleen K. Loo has received equipment support from Soterix for a clinical trial and funding from Australian NHRMC and Stanley medical research foundation for clinical trials of transcranial electrical stimulation. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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