Depression — challenges in primary care
Published in MedicineWise News
Date published: About this date
- Which antidepressant?
- What if the patient does not respond to initial treatment?
- How long should an antidepressant be continued?
- Using antidepressants safely and effectively in older patients
- Exercise and depression
- Case Study 73: Depression in primary care
- Other resources (includes links to support groups, etc)
During 2010–11, depression ranked second after hypertension among the chronic problems most frequently seen by Australian GPs. About two-thirds of the consultations for depression resulted in a prescription for an antidepressant, 40% involved counselling by the GP and 10% resulted in referral to a psychologist or other allied health practitioner, for example through the Better Access or Access to Allied Psychological Services (ATAPS) programs.1,2
Current guidelines endorse antidepressants for moderate-to-severe major depressive disorder (MDD).3,4 An antidepressant is also useful when depression is comorbid with an anxiety disorder; this comorbidity is as prevalent as depression on its own (see NPS News 65).5,6 Avoid antidepressant monotherapy if bipolar disorder is suspected; always assess if there is a history of mood elevation consistent with mania or hypomania.3,4 NPS Prescribing Practice Review 58 will include more information about diagnosing depressive disorders.
People with mild MDD are unlikely to benefit from an antidepressant. Pooled analyses of data from randomised controlled trials suggest that the margin of benefit of antidepressant over placebo increases with depression severity, and only reaches clinical significance among people with severe symptoms (see Figure 1); the data came from trials using fluoxetine, imipramine, nefazodone, paroxetine or venlafaxine.7,8
Non-drug treatments are suitable for most people
Non-drug treatments avoid the adverse effects of antidepressants. Offer a range of treatments, guided by patient preferences (NPS Prescribing Practice Review 58 will contain a table of options). Non-drug treatments require patient engagement to succeed. Options in mild-to-moderate MDD include short-term (e.g. 6–8 sessions) cognitive–behavioural therapy (CBT), guided self-help, computer-based CBT, and structured, supervised exercise.4,9 See Exercise and depression.
For people with moderate-to-severe MDD, the response rate when an antidepressant is combined with CBT or interpersonal therapy (IPT) is higher than with an antidepressant alone.4,10 The benefits of psychological therapies are likely to persist in the form of reduced relapse rates after completing treatment.11
There is no single drug that is the best first-line choice for depression. The selective serotonin reuptake inhibitors (SSRIs) are considered to have the most favourable balance of benefits and harms in moderate-to-severe MDD.4 When selecting a drug, discuss potential adverse effects (e.g. gastrointestinal upset, weight gain and sexual dysfunction) and perceptions of effectiveness and tolerability, considering the person’s previous experiences with antidepressants. 3,4 See Table 1 for significant differences in rates of adverse effects between common antidepressants.
Recommendations vary on whether non-SSRIs such as venlafaxine (Efexor-XR) are also a good first choice. Take into account the potential for venlafaxine to cause death in overdose and exacerbate hypertension or arrhythmias.3,4 The response rate to venlafaxine was 5% higher than to fluoxetine in a recent meta-analysis, but the authors concluded that the difference in efficacy was unlikely to be clinically significant. They also reported higher rates of stopping venlafaxine due to adverse effects.12
The newest antidepressants available on the Pharmaceutical Benefits Scheme, desvenlafaxine and duloxetine, are not demonstrably better than SSRIs and venlafaxine (see NPS RADARs on desvenlafaxine and duloxetine. Desvenlafaxine is similar to its parent, venlafaxine. Meta-analyses found lower response rates with duloxetine than escitalopram and that more people stopped treatment because of adverse effects with duloxetine than with SSRIs or venlafaxine.12,13
||Difference in adverse effect|
|Duloxetine||Higher rates of stopping due to adverse effects than SSRIs (e.g. nausea)|
|Mirtazapine||More weight gain than SSRIs|
|Paroxetine||Highest rates of discontinuation symptoms e.g. dizziness, nausea (equal to venlafaxine)|
|Sertraline||Highest rates of diarrhoea among SSRIs|
More nausea and vomiting than SSRIs
Highest rates of discontinuation symptoms e.g. dizziness, nausea (equal to paroxetine)
Higher rates of stopping due to adverse effects than SSRIs (e.g. nausea)
Allow up to 4 weeks for response to an antidepressant
If there is inadequate improvement in 4 weeks, first evaluate adherence. If response is absent or minimal after 4 weeks at a therapeutic dose, consider increasing the dose of the antidepressant within the recommended range, or switching to another antidepressant (e.g. if adverse effects are troublesome or the patient prefers to do so).3,4 Weekly follow-up may be helpful.4
Response to an antidepressant is noticeable typically within 2–4 weeks of starting treatment; about 25% will show no improvement after 4 weeks of treatment.4,14 If there is no improvement at all after 4 weeks, response to continuing treatment with the same antidepressant is unlikely.4 For those who do respond, symptoms may continue to improve for up to 12 weeks.15
When switching from an SSRI, initial options include a different SSRI, mirtazapine or venlafaxine (with the same considerations about safety described above). There is no overwhelming evidence for any particular choice. Consider the half-life of the drugs and potential for drug interactions when switching.4
Augmentation with psychological therapy in an option when there is inadequate response to drug treatment: adding or switching to a psychological therapy was as successful as adding or switching a drug in one major trial, STAR*D.16 A psychiatrist (e.g. through GP Psych Support, or call 1 800 200 588) can advise about a treatment plan in case of uncertainty.
High doses are not recommended
In a limited number of studies, the dose–response curves for SSRIs appear to be flat, with low doses as effective as higher doses.17 Nonetheless, it is reasonable to increase the dose within the recommended range when there has been a partial response and no troublesome adverse effects.4
Higher-than-recommended doses of SSRIs increase the rates of adverse effects and the risk of serotonin toxicity.18 In addition, there are recent warnings about the risk of arrhythmias (QT interval prolongation) with doses of citalopram higher than 40 mg daily or escitalopram higher than 20 mg daily19,20, and the risk of cardiovascular adverse effects with venlafaxine when the dose is higher than 150–200 mg daily.21
Evidence for combinations is inconsistent
Combining antidepressants, such as adding mirtazapine or mianserin to an SSRI, has been reported by many psychiatrists22 but this increases the risk of adverse effects and is not supported by consistent evidence.23 In the CO-MED trial, there was no advantage of the combination of venlafaxine with mirtazapine over escitalopram alone on remission rates at 12 weeks or 7 months, while the combination caused more adverse effects.24
Augmentation has a place in specialist care
There is evidence for augmenting antidepressant therapy with lithium or an antipsychotic when several trials of antidepressant monotherapy have failed; however, increased efficacy comes at the cost of an increase in adverse effects.4,25 Evidence for thyroid hormone (triiodothyronine) augmentation is inconclusive.4,26 Any combination therapy should be considered only in consultation with a psychiatrist.3,4,23
To reduce the risk of relapse, continue the antidepressant for 6–12 months after remission of symptoms.3,4 In clinical trials of stopping an antidepressant within one year of remission, about 40% of people who stopped, relapsed, compared with about 20% of people who continued with an antidepressant.27
People at high risk of recurrence should continue antidepressant treatment for 2–3 years, perhaps longer. Risk factors for recurrence include:
- residual depressive symptoms
- a history of 3 or more prior episodes, or 2 or more episodes in the last 5 years
- a history of severe depression (especially with psychotic symptoms or a serious suicide attempt).3,4
Individual circumstances and preferences must guide prescribing decisions; guideline recommendations are based largely on expert opinion rather than clinical trials.
Additional psychological therapy for relapse prevention, such as CBT or mindfulness therapy, appears to be as effective as long-term continuation of antidepressants and should be considered for people who have had multiple episodes of MDD.3,4
If stopping an antidepressant taper the dose gradually as stopping abruptly appears to cause more discontinuation symptoms; there is no good evidence to guide tapering.3,4,28 When stopping an SSRI or serotonin and noradrenaline reuptake inhibitor (SNRI) symptoms are usually mild and last 1–2 weeks.28
The rate of SSRI prescribing for Australians over 80 years is higher than for any other age group.29 Despite this, it appears that late-life depression is underdiagnosed. A study in Melbourne aged-care hostels found only half of the residents with current symptoms of MDD were receiving an antidepressant or any psychological treatment.30 A proportion of SSRI prescribing in this age group may be for dementia with mood disorder31—although there is limited evidence for this indication.
Antidepressants are effective for MDD among people aged 55 years and older, although the effect appears to be modest.32 Psychological therapies can also be effective, but are underused.30,33,34 As with younger people, non-drug treatments are first line in minor depression and mild MDD.4
Older patients experience antidepressant adverse effects more frequently than younger patients.3 The balance of benefits and harms needs to be assessed before starting therapy and regularly thereafter. Adverse effects such as nausea and dizziness are common, and falls and hyponatraemia can also occur.3,35,36 Criteria for continuing antidepressant use are otherwise the same as for younger patients (see above).4
A recent UK study of 60 000 people aged 65 to 100 years and diagnosed with depression found an increased risk of falls and fractures for people treated with any class of antidepressant compared with those who did not receive an antidepressant, with an absolute excess risk on the order of 1% per year.37 Another recent study of Dutch aged-care facility residents, found that the risk of falls leading to injury increased with higher doses of SSRIs.38
Antidepressants may be ineffective for people with dementia
For depression in people with dementia, sertraline or mirtazapine appear to be ineffective and other antidepressants have not been adequately assessed.39,40 In two trials involving people with dementia, improvements in depression symptoms were no different for sertraline, mirtazapine or placebo.41,42 Psychosocial interventions and environmental modification are an alternative, at least if depression is not severe.39
Supervised group physical activity is suitable for people with minor depressive symptoms or mild-to-moderate MDD.4 A meta-analysis of all relevant trials found a positive effect of exercise on depressive symptoms, although when limited to the 3 trials that were the most rigorously conducted, the benefit over non-exercise controls was moderate and did not reach statistical significance.43 Nonetheless, exercise has general health benefits and can provide an opportunity for therapeutic social interactions. See Box 1 for a list of resources for promoting physical activity.
The SMILE study illustrates a feasible exercise program for people with depression. Participants were sedentary adults with mild-to-moderate MDD.45 Exercise took the form of three 45-minute sessions of aerobic exercise (using a treadmill) per week for 16 weeks. Participants were randomised to home-based exercise with minimal but regular contact with study staff (n=53), supervised group exercise (n=51), sertraline (n=49) or placebo (n=49). After 4 months, depression remission rates were 40% for home-based exercise, 45% for supervised exercise, 47% for sertraline and 31% for placebo (see Figure 2). The difference between all 3 active treatment groups and placebo did not reach statistical significance (p=0.06), possibly because the study had too few participants to measure a small effect.44 At 1-year follow up, the remission rate was about 65% in all groups, including placebo.45
|Box 1. Resources to promote physical activity for people with depression|
The Black Dog Institute provides the following resources for encouraging people with depression to exercise:
The Heart Foundation coordinates group exercise activities in many parts of Australia:
A psychologist may be able to assist with motivation, activity scheduling and problem-solving to overcome barriers to exercise, for example as part of subsidised psychological consultations:
Expert reviewersA/Prof Grant Blashki Nossal, Institute for Global Health & Melbourne Sustainable Society Institute, University of Melbourne
Dr David King, Discipline of General Practice, School of Medicine, The University of Queensland
Dr John Dowden, Editor, Australian Prescriber
Dr Graham Emblen, GP, Toowoomba
Dr Sarah Gani, GP and Medical Educator, Blacktown
Benafsha Khariwala, Managing Editor, Journal of Pharmacy Practice and Research
A/Prof Jennifer Martin, Head PA-Southside Clinical School
Deborah Norton, QUM Pharmacist, West Vic DGP
Simone Rossi, Managing Editor, Australian Medicines Handbook
Any correspondence regarding content should be directed to NPS. Declarations of conflicts of interest have been soughtfrom all reviewers.
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- Slade T, Johnston A, Teesson M, et al. The Mental Health of Australians 2. Report on the 2007 National Survey of Mental Health and Wellbeing. Canberra: Department of Health and Ageing, 2009. (accessed 9 January 2012).
- Australian Institute of Health and Welfare Australian General Practice Statistics and Classification Centre. SAND abstract 147 from the BEACH program 2009–10: depressive disorders, management and comorbidities. Sydney: AGPSCC University of Sydney, 2010. (accessed 9 January 2012).
- Fournier JC, DeRubeis RJ, Hollon SD, et al. Antidepressant drug effects and depression severity: a patient-level meta-analysis. JAMA 2010;303:47–53.
- Kirsch I, Deacon BJ, Huedo-Medina TB, et al. Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration. PLoS Med 2008;5:e45.
- Bortolotti B, Menchetti M, Bellini F, et al. Psychological interventions for major depression in primary care: a meta-analytic review of randomized controlled trials. Gen Hosp Psychiatry 2008;30:293–302.
- Cuijpers P, Dekker J, Hollon SD, et al. Adding psychotherapy to pharmacotherapy in the treatment of depressive disorders in adults: a meta-analysis. J Clin Psychiatry 2009;70:1219–29.
- Spielmans GI, Berman MI, Usitalo AN. Psychotherapy versus second-generation antidepressants in the treatment of depression: a meta-analysis. J Nerv Ment Dis 2011;199:142–9.
- Gartlehner G, Hansen RA, Morgan LC, et al. Comparative benefits and harms of second-generation antidepressants for treating major depressive disorder: an updated meta-analysis. Ann Intern Med 2011;155:772-85.
- Schueler YB, Koesters M, Wieseler B, et al. A systematic review of duloxetine and venlafaxine in major depression, including unpublished data. Acta Psychiatr Scand 2011;123:247–65.
- Szegedi A, Jansen WT, van Willigenburg AP, et al. Early improvement in the first 2 weeks as a predictor of treatment outcome in patients with major depressive disorder: a meta-analysis including 6562 patients. J Clin Psychiatry 2009;70:344-53.
- Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry 2006;163:28–40.
- Thase ME, Friedman ES, Biggs MM, et al. Cognitive therapy versus medication in augmentation and switch strategies as second-step treatments: a STAR*D report. Am J Psychiatry 2007;164:739–52.
- Adli M, Baethge C, Heinz A, et al. Is dose escalation of antidepressants a rational strategy after a medium-dose treatment has failed? A systematic review. Eur Arch Psychiatry Clin Neurosci 2005;255:387–400.
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- Keks NA, Burrows GD, Copolov DL, et al. Beyond the evidence: is there a place for antidepressant combinations in the pharmacotherapy of depression? Med J Aust 2007;186:142–4.
- Rush AJ, Trivedi MH, Stewart JW, et al. Combining medications to enhance depression outcomes (CO-MED): acute and long-term outcomes of a single-blind randomized study. Am J Psychiatry 2011;168:689–701.
- Nelson JC, Papakostas GI. Atypical antipsychotic augmentation in major depressive disorder: a meta-analysis of placebo-controlled randomized trials. Am J Psychiatry 2009;166:980–91.
- Papakostas GI, Cooper-Kazaz R, Appelhof BC, et al. Simultaneous initiation (coinitiation) of pharmacotherapy with triiodothyronine and a selective serotonin reuptake inhibitor for major depressive disorder: a quantitative synthesis of double-blind studies. Int Clin Psychopharmacol 2009;24:19–25.
- Hansen R, Gaynes B, Thieda P, et al. Meta-analysis of major depressive disorder relapse and recurrence with second-generation antidepressants. Psychiatr Serv 2008;59:1121–30.
- Warner CH, Bobo W, Warner C, et al. Antidepressant discontinuation syndrome. Am Fam Physician 2006;74:449–56.
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- George K, Davison TE, McCabe M, et al. Treatment of depression in low-level residential care facilities for the elderly. Int Psychogeriatr 2007;19:1153–60.
- Nishtala PS, McLachlan AJ, Bell JS, et al. Determinants of antidepressant medication prescribing in elderly residents of aged care homes in Australia: a retrospective study. Am J Geriatr Pharmacother 2009;7:210–9.
- Tedeschini E, Levkovitz Y, Iovieno N, et al. Efficacy of antidepressants for late-life depression: a meta-analysis and meta-regression of placebo-controlled randomized trials. J Clin Psychiatry 2011;72:1660–8.
- Arean PA, Raue P, Mackin RS, et al. Problem-solving therapy and supportive therapy in older adults with major depression and executive dysfunction. Am J Psychiatry 2010;167:1391–8.
- Cuijpers P, van Straten A, Smit F. Psychological treatment of late-life depression: a meta-analysis of randomized controlled trials. Int J Geriatr Psychiatry 2006;21:1139–49.
- Jacob S, Spinler SA. Hyponatremia associated with selective serotonin-reuptake inhibitors in older adults. Annals Pharmacother 2006;40:1618–22.
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- Nelson JC, Devanand DP. A systematic review and meta-analysis of placebo-controlled antidepressant studies in people with depression and dementia. J Am Geriatr Soc 2011;59:577–85.
- Banerjee S, Hellier J, Dewey M, et al. Sertraline or mirtazapine for depression in dementia (HTA-SADD): a randomised, multicentre, double-blind, placebo-controlled trial. Lancet 2011;378:403–11.
- Weintraub D, Rosenberg PB, Drye LT, et al. Sertraline for the treatment of depression in Alzheimer disease: week-24 outcomes. Am J Geriat Psychiatry 2010;18:332–40.
- Mead GE, Morley W, Campbell P, et al. Exercise for depression. Cochrane Database Syst Rev 2009:CD004366.
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