Anxiety and depression in late life






Gerard J. BYRNE,BSc
(Med.), MBBS, PhD,
FRANZCP
Professor and Head of Psychiatry, School of Medicine, The University of Queensland, Brisbane Director, Older Persons’ Mental Health Service
Royal Brisbane & Women’s Hospital
Brisbane, AUSTRALIA

Anxiety and depression in late life


by G. J. Byrne, Australia



Although the prevalence of anxiety and depressive disorders among community-residing older adults is lower than in middle-aged persons, there are high rates of both in older people admitted to general hospitals, those receiving domiciliary care, and those residing in nursing homes. High rates of anxiety and depression also occur in older people with mild cognitive impairment and dementia. Evidence-based psychological and pharmacological treatments are available for the treatment of anxiety and depressive disorders in older people. These two treatment modalities show approximately equivalent efficacy, although drug treatments are generally preferred for older people with more severe depression and psychological treatments are generally preferred for older people with mild to moderate anxiety. Both interpersonal psychotherapy and cognitive behavioral therapy are effective in older people, although the latter is in more widespread use. Rational drug treatment of anxiety and depression in older people mainly involves the use of antidepressant medication, particularly the selective serotonin reuptake inhibitors. At present, it is unclear whether antidepressant medication is effective in patients with both dementia and depression. Electroconvulsive therapy remains an appropriate option for older depressed patients who have stopped eating or drinking, have psychotic symptoms, or are actively suicidal. Combination treatment with antidepressant medication and one of the psychological treatments is recommended although there is only limited supporting evidence in older people. Newer brain stimulation treatments such as transcranial magnetic stimulation are being trialed in older people with anxiety and depression, but in many places their use remains investigational. Prevention of both anxiety and depression in older people does seem feasible and a stepped-care program has shown promising results.

Medicographia. 2012;34:339-345 (see French abstract on page 345)


Background

_ Epidemiology
With increasing longevity in developed and most developing countries, both the proportion and the absolute number of older people are rising worldwide. Sex-specific mortality rates mean that population aging is accompanied by demographic feminization. This effect, in combination with cognitive aging, is likely to lead to increased rates of both anxiety and depression. However, in most national epidemiological studies, anxiety and depression fall in prevalence among community-residing individuals after the age of about 50 years (see Figure 1 page 340).1 The full explanation for this observation is yet to be elucidated, although selective mortality of people with anxiety and depressive disorders and changes in personality with advancing age are likely to contribute. Although personality is relatively stable over the adult lifespan, older adults do have lower neuroticism in comparison with younger adults.2 As neuroticism is the character trait most relevant for the development of anxiety and depression, it makes intuitive sense for the prevalence of these two disorders to decrease in late life. Despite these general observations, the trend toward lower rates of anxiety and depression in community-residing older people masks much higher rates of anxiety and depression among hospitalized older people, among those receiving domiciliary nursing care and those living in nursing homes. These individuals are rarely included in national epidemiological surveys. For example, in long-term care (nursing home) settings, the median prevalence of depressive symptoms was found to be 29%, while that of major depressive disorder was found to be 10%.3


Figure 1
Figure 1. 12-Month prevalence of anxiety and affective disordersby age.

After reference 1: Australian Bureau of Statistics 2007. National Survey of Mental Health & Well Being, Basic CURF, CD-ROM, ABS, Canberra. © Commonwealth
of Australia.



The most prevalent anxiety disorder in older people is generalized anxiety disorder (GAD). Simple or situational phobias also occur commonly, but most national surveys do not measure the prevalence of these due to the difficulty in establishing their clinical significance at cross-sectional interview. Less common anxiety disorders in late life include panic disorder, agoraphobia, social phobia, posttraumatic stress disorder, and obsessive-compulsive disorder. It has been proposed that the sympathetic nervous system becomes less responsive in old age, making panic attacks and panicky feelings less likely. The most prevalent depressive disorder in older people is major depressive disorder. Suicide rates are increased in older people with anxiety and depressive disorders and in many countries this is particularly true for older men.

_ Comorbidity
Although anxiety and depressive disorders can usually be distinguished from one another in older people, there is substantial comorbidity between the two. This likely reflects shared etiological factors, including polygenic influences, trait neuroticism, childhood adversity, adult adverse life events, physical illness, substance abuse, effects of medication, and cognitive impairment. It also reflects to some extent an overlap in symptoms, particularly between major depressive disorder and GAD. In addition, many older people have subthreshold mixtures of anxiety and depressive symptoms, which warrant the use of the rubric “mixed anxiety and depression.”

The prevalence of substance use disorders declines markedly in later life. This appears to be due to the combined effects of reduced income, reduced tolerance to the effects of alcohol and other drugs, and social disapproval. However, those older people with substance use disorders do commonly have an anxiety and depressive disorder as well. This is particularly true for abuse and dependence syndromes involving alcohol and prescribed hypnosedatives. Anxiety and depressive symptoms also occur commonly in older people with general medical conditions, including chronic obstructive lung disease, ischemic heart disease, and stroke. Because most anxiety and depressive disorders develop before middle age, older persons developing anxiety or depression for the first time in later life must be investigated for an underlying general medical condition. The prevalence of cognitive problems, including mild cognitive impairment and dementia, rises exponentially with advancing age. Both mild cognitive impairment and dementia are associated with high rates of anxiety and depressive symptoms and disorders.

Assessment

The majority of older people with anxiety and depression are seen in primary care settings. Where this is not the case, the assessment and management of an older person should be undertaken in collaboration with his or her general practitioner (primary care physician) because of the strong nexus between mental health and physical health in older people. A physical examination with special emphasis on neurological and cardiovascular function is recommended as part of the routine work-up.

It is important to check cognitive function in older people presenting with anxiety and depressive symptoms. Cross-sectional assessment of cognitive function is not complete in the absence of an informant interview, as many older people are not aware of the extent of their cognitive impairment. In addition, cognitive screening tests, other than the Informant Questionnaire for COgnitive Decline in the Elderly (IQCODE),4 do not establish the extent of cognitive change over time. Screening cognitive testing should be undertaken wherever practicable. There are many suitable scales available, including the Addenbrooke’s Cognitive Examination–Revised (ACE-R),5 which combines items similar to those in the Mini Mental State Examination (MMSE) with items that cover a broader range of brain functions.

It is often useful to obtain a quantitative estimate of the subjective severity of anxiety or depression using rating scales specifically developed for use in older people. Although several scales are now available, the most accessible are the Geriatric Depression Scale6 and the Geriatric Anxiety Inventory.7 Both are also available in 5-item short forms8,9 for rapid screening in general medical settings.





_ Investigations
General medical problems become more common with advancing age and must be excluded as potential causes and complications of anxiety and depression. Clinical judgment is required in ordering laboratory investigations and neuroimaging studies. However, the following blood tests are commonly requested: full blood examination, serum electrolytes, serum glucose, serum urea and creatinine, liver enzymes, thyroid stimulating hormone, serum vitamin B12, red cell folate and serum vitamin D. Magnetic resonance imaging is generally considered the neuroimaging study of choice in older people because of its ability to reveal the extent of white matter ischemic changes, although it is often more expensive and less accessible than computer tomographic brain imaging.

Treatment

_ General measures
The excessive use of caffeine-containing beverages, including coffee and cola drinks, is associated with clinically significant anxiety symptoms in vulnerable individuals. Although these substances are used less frequently in older people, they still occasionally act as exacerbating agents. In addition, excessive alcohol consumption is often associated with depressive symptoms, and withdrawal from alcohol is often associated with both anxiety and depressive symptoms. As a consequence, the initial management of depression or anxiety in older people should include consideration of their caffeine and alcohol intake. Use of amphetamines, cocaine, and narcotics is much less prevalent in most older populations, but is still worth considering in selected cases.

Many general medical conditions are associated with anxiety or depression, including ischemic heart disease, stroke, asthma, emphysema, diabetes mellitus, cancer, Alzheimer’s disease, and virus infections. Prescribed medications can lead to syndromal or subsyndromal depression or anxiety. Commonly implicated agents include corticosteroids; interferon; agents used in the treatment of cancer, such as interleukin 2; and agents used in the treatment of autoimmune disorders, such as tumor necrosis factor α. Sympathomimetic agents, including those used in treatment of asthma and chronic obstructive lung disease, commonly lead to anxiety symptoms. Thus, the management of anxiety and depression in older people should include consideration of any comorbid general medical disorders and any prescribed medication.

There are several nonspecific interventions that are likely to assist many older people with anxiety or depressive disorders; these include psycho education, sleep hygiene, and relaxation training. In addition, it is prudent to optimize cognitive function as part of a broader treatment plan for anxiety and depression in older people. This will often involve the cautious cessation of medications with anticholinergic or antihistaminic effects, which may impair cognition. Because benzodiazepines and related medications also have significant amnestic effects, their use should be minimized in older people.

Most treatments for anxiety and depression in older people can be carried out in primary care settings by appropriately trained general practitioners, clinical psychologists, and nurse practitioners. Cases of diagnostic uncertainty, treatment resistance, or high severity should be referred for specialist attention. Evidence from adult populations indicates that combination treatment with antidepressant medication and a psychological intervention works best, both during acute treatment and for relapse prevention. It is beyond the scope of this article to discuss the management of individual anxiety disorders.

_ Drug treatment
Although benzodiazepines are in widespread use for the treatment of anxiety symptoms and anxiety disorders in adults of all ages, they have a number of disadvantages. First of all, their efficacy has been demonstrated only in short-term studies and it is likely that they actually increase anxiety symptoms in the longer term through withdrawal effects and by limiting environmental exposure. Secondly, they are associated with falls, amnesia, disruption of sleep architecture, and confusion. Thus, if benzodiazepines are to be used, they should be reserved for short-term use, while initiating antidepressant therapy and planning psychological treatment.

Antidepressants are the preferred pharmacological treatment for both anxiety and depressive disorders in older people. There is little evidence to suggest that one antidepressant is superior in efficacy to another, so choice of agent is made mainly on the basis of past history of response and expected adverse effect profile. Some antidepressants are more activating whereas others are more sedating and these properties enable them to be tailored to treat patients with psychomotor retardation or agitation, respectively. The selective serotonin reuptake inhibitors (SSRIs) are first-line treatments for both anxiety and depressive disorders in older people. Commencement of SSRI treatment is commonly associated with an initial increase in jitteriness, anxiety or insomnia. This early worsening can be managed with a combination of psycho education and the short-term use of a benzodiazepine, such as oxazepam. While generally safer than tricyclic antidepressants and monoamine oxidase inhibitors, the SSRIs are associated with an increased risk of bleeding, hyponatremia, and falls in older people.10 Hyponatremia appears to occur more commonly in women and those on thiazide diuretics. Citalopram and escitalopram have been reported to be associated with prolongation of the electrocardiogram corrected QT (QTc) interval and cardiac arrhythmias in older people. As a consequence, the UK Medicines and Healthcare Products Regulatory Agency (MHRA) has recommended that citalopram be used in doses no greater than 20 mg daily and that escitalopram be used in doses no greater than 10 mg daily in people aged 65 years and over.11 By convention, older patients with insomnia as part of their anxiety or depression have been treated with more sedating antidepressants such as fluvoxamine or mirtazapine, which rely on antihistaminic properties to assist with sleep. However, newer drugs such as agomelatine, which work on the melatonergic and 5-HT2C systems, might offer an advantage in this situation.12 In older people with cognitive impairment, urinary hesitancy, or narrow-angle glaucoma, it is prudent to avoid antidepressants with significant anticholinergic effects, such as paroxetine, the older tricyclics, and monoamine oxidase inhibitors. However, if a tricyclic antidepressant is to be used to treat an anxiety or depressive disorder in late life, it is often preferable to use nortriptyline, as it seems to be associated with the best safety profile in older people. Low-potency antipsychotic medications, such as quetiapine, have sometimes been used in the management of anxiety symptoms. However, there is limited evidence for their use in older people. A meta-analysis of 9 short-term clinical trials of medication for the treatment of GAD in older people found that medication was superior to placebo with a pooled odds ratio of 0.32 (95% confidence interval [CI], 0.18-0.54).13 Antidepressants, benzodiazepines, and quetiapine all demonstrated short-term efficacy.

_ Augmentation strategies
Combined treatment with antidepressant medication and manual- based psychotherapy (cognitive behavior therapy [CBT] or interpersonal psychotherapy [IPT]) has been shown to improve efficacy both in the acute phase and during relapse prevention in major depression. It is likely that the same combination would also be associated with improved efficacy in the management of late-life anxiety disorders, although no methodologically sound clinical trials of combination treatment have been published. Other augmentation strategies for major depression include the use of mood stabilizers, such as lithium carbonate, sodium valproate, or an atypical antipsychotic. Although carbamazepine can also be used as an antidepressant augmentation agent, its multiple drug-drug interactions make it less suitable for use in older people. Lithium carbonate can be used as an augmentation agent in the acute treatment of major depression as well as in relapse prevention, including following a course of electroconvulsive therapy (ECT). The evidence base for combinations of antidepressants as an augmentation strategy is less secure in older people and best avoided. There is evidence for the use of thyroid hormone as an augmentation strategy in adults, although this must be approached cautiously as there are significant potential adverse effects, particularly in older people.

_ Complications of drug treatment
While the use of antidepressant medication is an important component of the treatment of both anxiety and depression in older people, it is often associated with adverse effects. A recently reported cohort study found increased mortality among older people treated with modern antidepressants, although confounding by indication might explain at least some of this effect.14 Importantly, the use of SSRIs to treat depression is associated with a reduced rate of suicide in older adults.15 Reduced bone mineral density together with an increased rate of falls and fractures has been reported in older people on antidepressant medication, including SSRIs.16 Hyponatremia also occurs commonly, particularly among older women on diuretic treatment. A large UK clinical trial has suggested that antidepressants might not be effective for the treatment of major depression in the context of dementia.17 However, this study did have methodological limitations, including the inclusion criterion of a score of 8 or more on the Cornell Scale for Depression in Dementia, rather than a formal diagnosis of major depression based on a diagnostic interview. Hence, the findings should not be taken as the last word on the treatment of depression in dementia. Because the use of antidepressants and other drugs to treat anxiety and depression in later life is often associated with dose-limiting adverse effects and modest efficacy, there may be a role in the future for pharmacogenomic assessment to help with the selection of antidepressant medication and dose range.

_ Psychotherapy
Psychological interventions are often preferred in older people with mild to moderate anxiety or depression. In relation to anxiety, there is evidence for the use of CBT. In relation to depression, there is evidence both for the use of CBT and for IPT. Some modifications are often needed when applying CBT in later life. These have been described in detail in specialist texts.18 Common modifications include increasing the font size in manuals to allow for visual impairment, increasing the number of sessions to allow for more summary and review work, and incorporating explicit learning and memory aids. In older people with mild cognitive impairment or dementia, the use of cognitive strategies can be quite challenging. In such cases, the clinician can employ the behavioral components of CBT alone. Relaxation techniques, behavioral activation, pleasant event scheduling, and exposure are well worth pursuing. Critical to the success of most behavioral interventions for anxiety disorders in older people is the use of explicit measures to overcome avoidance behavior. CBT and IPT are generally more effective when administered on an individual rather than a group basis. A meta-analysis of CBT for GAD in older people13 identified 11 small clinical trials with usable data and found that CBT was superior to control conditions with a pooled odds ratio of 0.33 (95% CI, 0.17-0.66).

Most of the available evidence indicates that IPT has satisfactory efficacy in the treatment of depression in older people and is generally well accepted in this age group.19 IPT is associated with improved outcomes for older depressed patients with cognitive impairment20 and with reduced caregiver burden.21 Research in middle-aged persons has demonstrated that IPT and CBT have similar efficacy.22 Despite these positive findings, IPT does not appear to be in widespread use for depression or anxiety in older people.

_ Stepped care
In the IMPACT study (Improving Mood Promoting Access to Collaborative Treatment), 1801 US primary care patients aged 60 years and over with SCID/DSM-IV (Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, fourth edition) major depressive disorder, dysthymic disorder, or both, were randomized to a 12-month collaborative care intervention or to usual depression care. The collaborative care program involved a depression care manager, a primary care physician, and a psychiatrist, who provided psycho education, behavioral activation, antidepressants, problem- solving therapy, and relapse-prevention strategies. The IMPACT intervention was found to be superior to usual depression care at 12-month, 18-month, and 24-month follow up.23 The findings from this study suggest that a multimodal, stepped-care approach can be effective for the management of depression in older people.

_ Brain stimulation
ECT is used to treat severely depressed older people and is highly effective in this context.24 It can be lifesaving in older people who are not eating and drinking, who are psychotic, or who are actively suicidal. ECT is generally well tolerated, apart from causing amnesia, which can take several weeks to resolve. Unfortunately, ECT remains a highly stigmatized treatment modality and it can be difficult to access in some places. Other methods of brain stimulation are gradually gaining clinical acceptance although none has the evidence base of ECT. These methods include trans-cranial magnetic stimulation (TMS), vagal nerve stimulation, and deep brain stimulation. At present, vagal nerve stimulation and deep brain stimulation are generally reserved for those with severe treatment- resistant disorders unresponsive to multiple courses of treatment, including ECT. TMS is in more widespread use and has the advantage over ECT that no general anesthetic is required. However, the available evidence suggests that ECT has greater efficacy than TMS.

Prevention

There is no known method for the universal, population-wide prevention of anxiety or depression in older people. However, there is some evidence for the indicated prevention of depression and anxiety in those showing early symptoms. A Dutch prevention study25,26 investigated 170 older primary care patients aged 75 years and over (mean age 81.4 years; 77% female) considered to be at high risk of anxiety or depressive disorder. Participants had a Center for Epidemiologic Studies– Depression (CES-D) scale score of 16 or greater (mean baseline CES-D score, 21.6), but did not have a current MINI (Mini International Neuropsychiatric Interview)/DSM-IV depressive or anxiety disorder. They were randomized to routine primary care or to stepped care. Stepped care consisted of 3- month cycles of watchful waiting, bibliotherapy, problem-solving treatment, and antidepressant medication provided over a 12-month period. The intervention halved the 12-month incidence of depressive and anxiety disorders with a number-needed- to-treat of 8.3 and at a cost (in 2007 euros) of €4297 per depression- and anxiety-free year.

There is also evidence for the selective prevention of depression in specific contexts, including macular degeneration. In a US study,27 206 older people (mean age 81 years) with neovascular macular degeneration were randomized to usual care or 6 sessions of problem-solving treatment over 8 weeks. Problem-solving treatment was associated with a 50% reduction in incident depression at 2-month follow-up. The evidence for prevention of completed suicide in older people is meager, although the PROSPECT study (Prevention Of Suicide in Primary care Elderly: Collaborative Trial)28 demonstrated some reduction in suicidal ideation in older depressed people treated with antidepressants and/or psychotherapy.

Conclusion

Anxiety and depressive disorders are not uncommon in later life and frequently complicate the common medical problems of later life. Many patients can be treated successfully with psychotherapy alone or with antidepressant medication in combination with psychotherapy. _


References
1. Australian Bureau of Statistics 2007. National Survey of Mental Health & Well Being, Basic CURF, CD-ROM, ABS, Canberra.
2. Costa PT, McCrae RR. Personality in adulthood: a six-year longitudinal study of self-reports and spouse ratings on the NEO Personality Inventory. J Pers Soc Psychol. 1988;54(5):853-863.
3. Seitz D, Purandare N, Conn D. Prevalence of psychiatric disorders among older adults in long-term care homes: a systematic review. Int Psychogeriatr. 2010; 22(7):1025-1039.
4. JormAF, Scott R, Cullen JS,MacKinnon AJ. Performance of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) as a screening test for dementia. Psychol Med. 1991;21:785-790.
5. Mioshi E, Dawson K, Mitchell J, Arnold R, Hodges JR. The Addenbrooke’s Cognitive Examination Revised (ACE-R): a brief cognitive test battery for dementia screening. Int J Geriatr Psychiatry. 2006;21:1078-1085.
6. Yesavage JA, Brink TL, Rose TL, et al. Development and validation of a geriatric depression screening scale: a preliminary report. J Psychiatr Res.1983;17(1): 37-49.
7. Pachana NA, Byrne GJ, Siddle H, Koloski N, Harley E, Arnold E. Development and validation of the Geriatric Anxiety Inventory. Int Psychogeriatr. 2007;19(1): 103-114.
8. Sheikh JI, Yesavage JA. Geriatric Depression Scale (GDS): recent evidence and development of a shorter version. In: Brink TL (ed). Clinical Gerontology: A Guide to Assessment and Intervention. New York, NY: The Haworth Press; 1986:165- 173.
9. Byrne GJ, Pachana NA. Development and validation of a short form of the Geriatric Anxiety Inventory – the GAI-SF. Int Psychogeriatr. 2011;23(1):125-131.
10. Kerse N, Flicker L, Pfaff JJ, et al. Falls, depression and antidepressants in later life: a large primary care appraisal. PLoS ONE. 2008;3(6):e2423.
11. Medicines and Healthcare Products Regulatory Agency. Drug Safety Update. 2011;5(5):O2. http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/ CON137769. Accessed online Dec 30, 2011.
12. Quera-Salva MA, Lemoine P, Guilleminault C. Impact of the novel antidepressant agomelatine on disturbed sleep-wake cycles in depressed patients. Hum Psychopharmacol. 2010;25(3):222-229.
13. Gonçalves DC, Byrne GJ. Interventions for generalized anxiety disorder in older adults: systematic review and meta-analysis. J Anxiety Disord. 2012;26(1): 1-11.
14. Coupland C, Dhiman P, Moriss R, Arthur A, Barton G, Hippisley-Cox J. Antidepressant use and risk of adverse outcomes in older people: population based cohort study. BMJ. 2011;343:d4551.
15. Barbui C, Esposito E, Cipriani A. Selective serotonin reuptake inhibitors and risk of suicide: a systematic review of observational studies. CMAJ. 2009;180:291- 297.
16. Richards JB, Papaioannou A, Adachi JD, et al; Canadian Multicentre Osteoporosis Study Research Group. Effect of selective serotonin reuptake inhibitors on the risk of fracture. Arch Intern Med. 2007;167(2):188-194.
17. Banerjee S, Hellier J, Dewey M, et al. Sertraline or mirtazapine for depression in dementia (HTA-SADD): a randomised, multicenter, double-blind, placebocontrolled trial. Lancet. 2011;378:403-411.
18. Laidlaw K, Thompson LW, Gallagher-Thompson D, Dick-Siskin L. Cognitive behaviour therapy with older people. Chichester,England: JohnWiley&Sons; 2003.
19. van Schaik DJ, van Marwijk HW, Beekman AT, de Haan M, van Dyck R. Interpersonal psychotherapy (IPT) for late-life depression in general practice: uptake and satisfaction by patients, therapists and physicians. BMC Fam Pract. 2007;8:52.
20. Carreira K, Miller MD, Frank E, et al. A controlled evaluation of monthly maintenance interpersonal psychotherapy in late-life depression with varying levels of cognitive function. Int J Geriatr Psychiatry. 2008;23:1110-1113.
21. Garand L, Dew MA, Eazor LR, DeKosky ST, Reynolds CF. Caregiving burden and psychiatric morbidity in spouses of persons with mild cognitive impairment. Int J Geriatr Psychiatry. 2005;20:512-522.
22. Luty SE, Carter JD, McKenzie JM, et al. Randomised controlled trial of interpersonal psychotherapy and cognitive-behavioural therapy for depression. Br J Psychiatry. 2007;190:496-502.
23. Hunkeler EM, Katon W, Tang L, et al. Long term outcomes from the IMPACT randomised trial for depressed elderly patients in primary care. BMJ. 2006;332 (7536):259-263.
24. van derWurff FB, Stek ML, HoogendijkWJ, Beekman AT. The efficacy and safety of ECT in depressed older adults: a literature review. Int J Geriatr Psychiatry. 2003;18(10):894-904.
25. van’t Veer-Tazelaar PJ, van Marwijk HW, van Oppen P, et al. Stepped-care prevention of anxiety and depression in late life. A randomized controlled trial. Arch Gen Psychiatry. 2009;66(3):297-304.
26. van’t Veer-Tazelaar P, Smit F, van Hout H, et al. Cost-effectiveness of a stepped care intervention to prevent depression and anxiety in late life: randomised trial. Br J Psychiatry. 2010;196:319-325.
27. Rovner BW, Casten RJ, Hegel MT, Leiby BE, Tasman WS. Preventing depression in age-related macular degeneration. Arch Gen Psychiatry. 2007;64(8): 886-892.
28. Alexopoulos GS, Reynolds CF, Bruce ML, et al; PROSPECT Group. Reducing suicidal ideation and depression in older primary care patients: 24-month outcomes of the PROSPECT study. Am J Psychiatry. 2009;166:882-890.


Keywords: antidepressant; anxiety; augmentation strategy; brain stimulation; combination therapy; depression; elderly; psychological intervention; stepped care