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BMJ Clinical Evidence logoLink to BMJ Clinical Evidence
. 2007 Jun 15;2007:1003.

Depression in adults: drug and physical treatments

Corrado Barbui 1,#, Rob Butler 2,#, Andrea Cipriani 3,#, John Geddes 4,#, Simon Hatcher 5,#
PMCID: PMC2943802  PMID: 19454086

Key Points

Depression may affect up to 10% of the population, with half of affected people having recurrence of their symptoms.

In mild to moderate depression, there is no reliable evidence that any one treatment is superior in improving symptoms of depression, but the strength of evidence supporting different treatments varies.

Tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors, reboxetine, and venlafaxine improve symptoms in the short term. However, long term studies are lacking.

  • No one class or individual antidepressant has been shown to be more effective than the others in the short term, but adverse effects vary between classes.

  • St John's Wort may have similar efficacy compared with antidepressants, but preparations vary and drug interactions can occur.

  • We don't know if exercise is beneficial in people with mild to moderate depression.

CAUTION: Tricyclic antidepressants and SSRIs may induce or worsen suicidal ideation and behaviour, and agitation after initiation of treatment.

We don't know whether adding lithium or pindolol to other antidepressant drugs reduces symptoms in people with treatment resistant depression.

Continuing prescription antidepressant drugs reduces the risk of relapse after recovery.

About this condition

Definition

Depressive disorders are characterised by persistent low mood, loss of interest and enjoyment, and reduced energy. They often impair day to day functioning. Most RCTs assessed in this review classify depression using the Diagnostic and statistical manual of mental disorders (DSM-IV) or the International classification of mental and behavioural disorders (ICD-10). DSM-IV divides depression into major depressive disorder or dysthymic disorder. Major depressive disorder is characterised by one or more major depressive episodes (i.e. at least 2 weeks of depressed mood or loss of interest accompanied by at least 4 additional symptoms of depression). Dysthymic disorder is characterised by at least 2 years of depressed mood for more days than not, accompanied by additional symptoms that do not reach the criteria for major depressive disorder. ICD-10 divides depression into mild to moderate or severe depressive episodes. Mild to moderate depression is characterised by depressive symptoms and some functional impairment. Severe depression is characterised by additional agitation or psychomotor retardation with marked somatic symptoms. Treatment resistant depression is defined as an absence of clinical response to treatment with a tricyclic antidepressant at a minimum dose of 150 mg daily of imipramine (or equivalent drug) for 4-6 weeks. In this review, we use both DSM-IV and ICD-10 classifications, but treatments are considered to have been assessed in severe depression if the RCT included inpatients. Older adults: Older adults are generally defined as people aged 65 years or older. However, some of the RCTs of older people in this review included people aged 55 years or over. The presentation of depression in older adults may be atypical: low mood may be masked and anxiety or memory impairment may be the principal presenting symptoms. Dementia should be considered in the differential diagnosis of depression in older adults. Treating depressive disorders in adults: Depressive disorders are generally treated with a range of drug, physical, and psychological treatments. For coverage of psychological treatments (including drug treatments v psychological treatments) and for coverage of combined drug and psychological treatment, see review on depression in adults: psychological treatments and care pathways. Population: This review does not cover intervention in women with postnatal depression (see review on postnatal depression), seasonal affective disorder, or depression owing to a physical illness such as stroke or substance abuse.

Incidence/ Prevalence

Depressive disorders are common, with a prevalence of major depression between 5% and 10% of people seen in primary care settings. Two to three times as many people may have depressive symptoms but do not meet DSM-IV criteria for major depression. Women are affected twice as often as men. Depressive disorders are the fourth most important cause of disability worldwide, and are expected to become the second most important by 2020. Older adults: Between 10% and 15% of older people have depressive symptoms, although major depression is relatively rare in older adults.

Aetiology/ Risk factors

The causes of depression are uncertain, but are thought to include both childhood events and current psychosocial adversity. Recent studies suggest that genetic factors may also be important, indicating that several chromosomal regions may be involved. Phenotypes, however, do not seem to exhibit classic Mendelian inheritance. Psychiatric research has also focused on the role that psychosocial factors, such as social context and personality dimensions, have in depression. Many theories emphasise the importance of temperament (differences in the adaptive systems), which can increase vulnerability to mood disturbances. Impairment in social relationships, gender, socioeconomic status, and dysfunctional cognition may also have a role. It seems that integrative models, which take into account the interaction of biological and social variables, offer the most reliable way to approach the complex aetiology of depression.

Prognosis

About half of people suffering a first episode of major depressive disorder experience further symptoms in the next 10 years. Older adults: One systematic review (search date 1996, 12 prospective cohort studies, 1268 people, mean age 60 years) found that the prognosis may be especially poor in elderly people with a chronic or relapsing course of depression. Another systematic review (search date 1999, 23 prospective cohort studies in people aged 65 years and over, including 5 identified by the first review) found that depression in older people was associated with increased mortality (15 studies; pooled OR 1.73, 95% CI 1.53 to 1.95).

Aims of intervention

To improve mood, social and occupational functioning, and quality of life; to reduce morbidity and mortality; to prevent recurrence of depressive disorder; and to minimise adverse effects of treatment.

Outcomes

Depressive symptoms rated by the depressed person and clinician; social functioning; occupational functioning; quality of life; admission to hospital; rates of self harm; relapse of depressive symptoms; rates of adverse events. RCTs often use continuous scales to measure depressive symptoms (such as the Hamilton Depression Rating Scale [HAM-D] and the Clinical Global Impression Scale [CGI]). A reduction in score of 50% or more on the HAM-D or a CGI score of 1 (very much improved) or 2 (much improved) is generally considered a clinically important response to treatment. Many RCTs express results in terms of effect size. Older adults: The HAM-D is not ideal for older people because it includes several somatic items that may be positive in older people who are not depressed. It has been the most widely used scale, although specific scales for elderly people (such as the Geriatric Depression Scale [GDS]) avoid somatic items.

Methods

BMJ Clinical Evidence search and appraisal April 2006. The following databases were used to identify studies for this review: Medline 1966 to April 2006, Embase 1980 to April 2006, Psychinfo 1980 to April 2006, and The Cochrane Library and Cochrane Central Register of Controlled Clinical Trials Issue 1, 2006. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and National Institute for Health and Clinical Excellence (NICE). Abstracts of the studies retrieved were assessed independently by two information specialists using predetermined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews and RCTs in any language, at least single blinded, and containing more than 20 individuals of whom more than 80% were followed up. There was no minimum length of follow up required to include studies. We excluded all studies described as "open", "open label", or not blinded unless blinding was impossible. We also did a search for cohort studies on specific harms of named interventions. In addition we use a regular surveillance protocol to capture harms alerts from organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the review as required. In this review, studies are included under the heading older adults if they specifically included people aged over 55 years.

Glossary

Augmentation

involves adding a medication to enhance the effects of another.

Continuation treatment

Continuation of treatment after successful resolution of a depressive episode to prevent relapse.

Dysthymic disorder

Characterised by at least 2 years of depressed mood for more days than not, accompanied by additional symptoms that do not reach the criteria for major depressive disorder.

Effect size

This expresses the degree of overlap between the range of scores in the control and experimental groups. The effect size can be used to estimate the proportion of people in the control group who had a poorer outcome than the average person in the experimental group; a proportion of 50% or less indicates that the treatment has no effect.

Major depressive disorder

Characterised by one or more major depressive episodes (i.e. at least 2 weeks of depressed mood or loss of interest accompanied by at least 4 additional symptoms of depression).

Mild to moderate depression

Characterised by depressive symptoms and some functional impairment.

Severe depression

Characterised by agitation or psychomotor retardation in addition to depressive symptoms and functional impairment with marked somatic symptoms. Treatments are considered to have been assessed in severe depression if the RCT included inpatients.

Depression in adults: psychological treatments and care pathways

Postnatal depression

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients.To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.

Contributor Information

Dr Corrado Barbui, Section of Psychiatry and Clinical Psychology, University of Verona, Verona, Italy.

Dr Rob Butler, University of Auckland and Waitemata Health, Auckland, New Zealand.

Dr Andrea Cipriani, Section of Psychiatry and Clinical Psychology, University of Verona, Verona, Italy.

Dr John Geddes, Department of Psychiatry, University of Oxford, Oxford, UK.

Dr Simon Hatcher, University of Auckland, Auckland, New Zealand.

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BMJ Clin Evid. 2007 Jun 15;2007:1003.

Electroconvulsive therapy

Summary

One systematic review in people with moderate to severe depressive disorder, many of whom were inpatients, found that electroconvulsive therapy improved symptoms over 1–6 weeks' treatment compared with simulated electroconvulsive therapy or antidepressant drugs. The review found that bilateral electroconvulsive therapy improved symptoms compared with unilateral electroconvulsive therapy, and that high dose electroconvulsive therapy was more effective than low dose. The degree of reported short term cognitive impairment seemed to be inversely related to treatment efficacy. Another systematic review provided insufficient evidence to assess electroconvulsive therapy in older adults. Because electroconvulsive therapy may be unacceptable to some people, and because it is a short term treatment, there is consensus that it should normally be reserved for people who cannot tolerate or have not responded to antidepressant drug treatment, although it may be useful when a rapid response is required.

Benefits

We found five systematic reviews. The most comprehensive systematic review (search date 2001) evaluated the efficacy and safety of electroconvulsive therapy (ECT) in younger and older adults with severe depression, primarily inpatients. The review used change in symptoms on a continuous scale as the primary outcome measure (see comment below).

Electroconvulsive therapy versus simulated electroconvulsive therapy:

The review found that ECT significantly improved symptoms compared with simulated ECT at the end of 1– 6 weeks' treatment (6 RCTs, 256 people; mean difference in Hamilton Depression Rating Scale [HAM-D] score 9.7, 95% CI 5.7 to 13.5 with ECT v simulated ECT).

Electroconvulsive therapy versus prescription antidepressant drugs:

The review found that ECT significantly improved symptoms compared with antidepressant drugs (tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, phenelzine, and trytophan) over 3–12 weeks (18 RCTs, 1144 people, mean difference in HAM-D score 5.2, 95% CI 1.4 to 8.9).

Different regimens of electroconvulsive therapy:

The review found that bilateral ECT significantly improved symptoms compared with unilateral ECT (22 RCTs, 1408 people, mean difference in HAM-D score 3.6, 95% CI 2.2 to 5.2). High dose ECT also significantly improved symptoms compared with low dose (7 RCTs, 342 people, mean difference in HAM-D score 4.1, 95% CI 2.4 to 5.9). The review found no significant difference in outcomes between twice weekly and three times weekly treatment, or between brief pulse waveform and sine wave.

Older adults:

We found one systematic review, which identified poor quality RCTs, with unclear methods of randomisation and assessment. The review stated that no firm conclusions could be drawn about the effects of ECT in older adults (search date 2000, 3 RCTs, 83 people aged > 60 years, with or without co-morbid illness).

Harms

The review could not perform a meta-analysis assessing effects on cognitive function because cognitive function was inconsistently assessed.

Electroconvulsive therapy versus simulated electroconvulsive therapy:

One RCT identified by the review suggested that ECT was more likely to impair cognitive functioning immediately after treatment than simulated ECT, but found no significant difference in cognitive functioning at 6 months.

Electroconvulsive therapy versus prescription antidepressant drugs:

One RCT identified by the review found that ECT was more likely to impair cognitive functioning immediately after treatment than antidepressant drug treatment, and another RCT found no significant difference in cognitive function. The RCTs are likely to have been underpowered to detect a clinically important difference. The review found that significantly more people taking antidepressant drugs compared with ECT withdrew from treatment (OR 0.41, 95% CI 0.12 to 0.88).

Different regimens of electroconvulsive therapy:

Bilateral ECT and high dose ECT were more likely to result in short term cognitive impairment than unilateral ECT and low dose ECT. Data on long term cognitive functioning were limited.

Older adults:

The RCTs identified by the review provided no reliable information on adverse effects.

Comment

To aid interpretation of results, the reviewers calculated standardised weighted mean differences and translated them into mean differences in symptoms on the HAM-D. Many of the RCTs included in the systematic review were small and old. There was substantial clinical heterogeneity among participants (diagnostic criteria used, severity of depression, inpatients and outpatients, previous treatments) and the modes of treatment compared (electrode placement, dose, waveform, frequency of administration, duration of treatment), but the review did not formally assess statistical heterogeneity.

Clinical guide:

Because ECT may be unacceptable to some people, and because it is a short term treatment, there is consensus that it should normally be reserved for people who cannot tolerate or have not responded to antidepressant drug treatment, when a rapid response is required.

Substantive changes

Electroconvulsive therapy (in severe depression) Two systematic reviews added. Categorisation unchanged (Beneficial).

BMJ Clin Evid. 2007 Jun 15;2007:1003.

Monoamine oxidase inhibitors versus other prescription antidepressant drugs in atypical depressive disorders

Summary

One systematic review found that monoamine oxidase inhibitors were less effective than tricyclic antidepressants in people with severe depressive disorders. However, two reviews found that monoamine oxidase inhibitors are more effective in atypical depressive disorders with biological features such as increased sleep and increased appetite.

Benefits

Monoamine oxidase inhibitors versus tricyclic antidepressants:

We found three systematic reviews. The first review (search date 1997, 150 RCTs, ≥ 16 000 people with major depression) found no significant difference in overall effectiveness between tricyclic antidepressants (TCAs) and newer antidepressants including monoamine oxidase inhibitors (MAOIs; see benefits of selective serotonin reuptake inhibitors). The second review (search date not reported, 55 RCTs) compared MAOIs versus TCAs in people aged 18–80 years with mild to moderate or severe depression. It found that MAOIs were less effective than TCAs in people with severe depressive disorders. However, the review found that MAOIs may be more effective in atypical depressive disorders (depressive disorders with reversed biological features [e.g. increased sleep, increased appetite, mood reactivity, and rejection sensitivity]). The third review (search date 2004, 4 RCTs, 236 people with atypical depression) found that MAOIs were significantly more effective for treating atypical depression compared with imipramine (effect size 0.27, 95% CI 0.16 to 0.42; response rates: 83/116 [71%] with MAOIs v 55/120 [46%] with imipramine).

Monoamine oxidase inhibitors versus selective serotonin reuptake inhibitors:

See benefits of selective serotonin reuptake inhibitors.

Harms

Monoamine oxidase inhibitors versus tricyclic antidepressants:

The first and third reviews gave no information on adverse effects. The second review found that MAOIs were associated with a similar level of overall adverse effects as TCAs. Adverse effects associated with MAOIs included hypotension, dizziness, mydriasis, piloerection, oedema, tremor, anorgasmia, and insomnia.

Monoamine oxidase inhibitors versus selective serotonin reuptake inhibitors:

See harms of selective serotonin reuptake inhibitors.

Comment

See comment on prescription antidepressant drugs versus placebo.

Clinical guide:

MAOIs are one of the oldest classes of antidepressants. MAOIs act by inhibiting the activity of monoamine oxidase preventing the breakdown of monoamine neurotransmitters. There are two isoforms of monoamine oxidase, MAO-A and MAO-B. The early MAOIs inhibited monoamine oxidase irreversibly. When they react with monoamine oxidase, they permanently deactivate it, and the enzyme cannot function until it has been replaced by the body, which can take about 2 weeks. A few newer MAOIs, notably moclobemide, are reversible, meaning that they can inhibit the enzyme for a time, allowing the enzyme to function once more. In addition, older MAOIs inhibit both MAO-A and MAO-B equally, but moclobemide targets only MAO-A. MAOIs are mostly used for atypical depression, but are used less frequently because they usually require specific dietary restrictions as they can, when combined with certain foods, cause a sudden, large increase in blood pressure, or hypertensive crisis.

Substantive changes

Monoamine oxidase inhibitors versus other prescription antidepressant drugs One systematic review added. Benefits and harms sections enhanced. Categorisation unchanged (Beneficial).

BMJ Clin Evid. 2007 Jun 15;2007:1003.

Prescription antidepressant drugs versus placebo

Summary

Systematic reviews and subsequent RCTs in people aged 18 years or over in primary and secondary care found that prescription antidepressant drugs (tricyclic antidepressants [including low dose tricyclic antidepressants], selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, or venlafaxine) were effective for treatment of all grades of depressive disorders compared with placebo. However, the most robust available evidence of efficacy of treatment with antidepressant drugs is in the pharmacological management of moderate and severe depression. One systematic review and two subsequent RCTs in people aged 55 years or over with all grades of depressive disorder found that tricyclic antidepressants, selective serotonin reuptake inhibitors, or monoamine oxidase inhibitors reduced the proportion of people who failed to recover over 26–49 days compared with placebo. The reviews gave little information on severe adverse effects of antidepressant drugs compared with placebo. There is evidence of publication bias in trials of selective serotonin reuptake inhibitors. Current evidence indicates no clear relationship between selective serotonin reuptake inhibitors and increased risk for suicide in adults, but selective serotonin reuptake inhibitors and tricyclic antidepressants may induce or worsen suicidal ideation and behaviour during the early phases of treatment. This may be because of increased agitation and activation. In children and adolescents, selective serotonin reuptake inhibitors generally increase adverse events compared with placebo, and the safety of these drugs is currently under review by regulatory authorities in several countries.

Benefits

We found six systematic reviews and seven subsequent RCTs. All found that antidepressant drugs significantly improved depressive symptoms compared with placebo. The first review (search date 1995, 49 RCTs in people aged 18–70 years with mild to moderate or severe depressive disorders) included five RCTs in people admitted to hospital (probably with severe depressive disorders), 40 RCTs in a setting outside hospital, one in both settings, and three that did not specify the setting. All RCTs identified by the review were of at least 4 weeks' duration and included three-way comparisons, including two antidepressant drugs (tricyclic antidepressants [TCAs], selective serotonin reuptake inhibitors [SSRIs], or monoamine oxidase inhibitors [MAOIs]) and placebo. The review only included RCTs that measured improvement in depressive symptoms using validated scales such as the Hamilton Depression Rating Scale (HAM-D) and Montgomery–Asberg Depression Rating Scale. It found that, on average, 69% of people taking placebo had worse outcomes over a mean of 6 weeks than the average person taking antidepressant drugs (mean effect size 0.5 for change in score with antidepressant drugs v placebo; see comment below). The second review (search date 2000, 35 RCTs, none included in the first review, 2013 people aged ≥ 18 years with all grades of depression, some with a physical illness) compared low dose (75–100 mg/day) TCAs (amitriptyline, clomipramine, doxepin, dosulepin [dothiepin], imipramine, lofepramine, trimipramine) versus placebo. It found that low dose TCAs significantly increased the proportion of people who responded at 4 weeks and at 3–12 months compared with placebo (response defined as ≥ 50% reduction in symptoms measured on a validated scale; at 4 weeks: 274/603 [45%] with TCAs v 159/557 [28%] with placebo; RR 1.65, 95% CI 1.36 to 2.00; at 3–12 months: 40/76 [53%] with TCAs v 18/77 [23%] with placebo; RR 2.14, 95% CI 1.41 to 3.26; results not intention to treat). The significant difference in response rates between low dose TCAs and placebo was not maintained when an intention to treat analysis based on the worst case scenario was performed. The third review (search date 1998, 150 RCTs, ≥ 16 000 people with major depression, see comment below) compared newer antidepressants (SSRIs [43 RCTs], MAOIs, or venlafaxine) versus placebo for at least 6 weeks. Response was defined as a 50% reduction in depression rating scale score or a Clinical Global Impression Scale (CGI) score of 1 (very much improved) or 2 (much improved). The review found that newer antidepressants significantly increased the proportion of people who responded compared with placebo (51% with newer antidepressants v 31% with placebo; RR 1.6, 95% CI 1.5 to 1.7). The third review also performed a separate analysis of results for people in primary care. It found that results remained significant; the average response rate was 63% with newer agents, 35% with placebo, and 60% with TCAs (RR for SSRIs v placebo 1.6, 95% CI 1.2 to 2.1). The fourth review (search date 1997, 15 RCTs, none included in the other reviews, some comparing two antidepressants v placebo, 1871 people aged ≥ 18 years) compared antidepressant and other drugs (TCAs [5 RCTs], SSRIs [4 RCTs], MAOIs [3 RCTs], other [2 RCTs]) versus placebo in people with dysthymia (chronic mild depressive disorders). It found that antidepressant or other drugs significantly increased the proportion of people who responded to treatment over 4–12 weeks compared with placebo (response defined as a 50% reduction in HAM-D score or scoring 1 or 2 on item 2 of the CGI score; RR 1.9, 95% CI 1.6 to 2.3; NNT 4, 95% CI 3 to 5). The fifth review found that SSRIs plus pindolol (7.5–15.0 mg/day) significantly increased the proportion of people with early clinical response compared with SSRIs plus placebo (search date 2001, 5 RCTs, 405 people aged > 18 years with depressive illness; proportion with early clinical response: 66/187 [35%] people with SSRIs plus pindolol v 32/187 [17%] people with SSRIs plus placebo; OR 2.8, 95% CI 1.4 to 5.7; NNT 6, 95% CI 4 to 20, see comment below). The review found no significant difference between SSRIs plus pindolol and SSRIs plus placebo in late clinical response (7 RCTs, 187 people aged > 18 years with depressive illness; proportion with late clinical response: 142/208 [68%] people with SSRIs plus pindolol v 124/206 [60%] people with SSRIs plus placebo; OR 1.4, 95% CI 0.8 to 2.7). The sixth review (search date 2004, 15 RCTs, 2753 people aged ≥ 18 years in primary care for depression) compared TCAs versus placebo (10 RCTs), SSRIs versus placebo (3 RCTs), and TCAs and SSRIs with placebo (2 RCTs). The review found that both TCAs and SSRIs were significantly more effective in treating depression compared with placebo (TCA v placebo: SMD for depression scores: –0.42, 95% CI –0.55 to –0.30; RR for improvement 1.26, 95% CI 1.12 to 1.42; 323/535 [60%] with TCAs v 216/460 [47%] with placebo; SSRI v placebo: RR for improvement: 1.37, 95% CI 1.21 to 1.55, 310/552 [56%] with SSRIs v 231/562 [41%] with placebo). There were several definitions used to describe “improvement”: four definition used greater than 50% reduction in the Montgomery–Asberg Depression Rating Scale (MADRS), greater than 50% reduction in Hamilton Depression Rating Scale (HAM-D), greater than 7 on the HAM-D scale, and 4 points or greater on HAM-D; and three definitions used global evaluation of improvement. We found three subsequent RCTs of reboxetine, two RCTs of escitalopram, one RCT of pindolol (as add on treatment to milnacipran), and one RCT of duloxetine compared with placebo. The first subsequent RCT (56 people aged 18–65 years admitted to hospital, probably with severe depressive disorders, mean HAM-D score > 35) compared reboxetine (6 mg/day for 1 day increasing to 10 mg over 3 days) versus placebo for 6 weeks' treatment. It found that reboxetine significantly increased the proportion of people who responded at 6 weeks compared with placebo (response defined as ≥ 50% reduction in HAM-D score: 74% with reboxetine v 20% with placebo; P < 0.001). The second subsequent RCT (258 people aged 18–65 years admitted to hospital with severe depression) compared three interventions: reboxetine 4–8 mg daily (84 people), desipramine 100–200 mg daily (89 people), and placebo (84 people). It found that reboxetine at any dose significantly increased the proportion of people who responded over 4 weeks compared with placebo (response defined as ≥ 50% reduction on continuous rating scale assessed by HAM-D: 60% with reboxetine v 35% with placebo; assessed by CGI score: 51% with reboxetine v 22% with placebo; P < 0.05 for response on either scale with reboxetine v placebo). The third subsequent RCT (381 people aged 18–65 years with major depressive disorder without psychotic features) assessed the effects of reboxetine 8–10 mg daily, paroxetine 20–40 mg daily, and placebo on social functioning. It found that reboxetine significantly improved mean Social Adaptation Self Evaluation Scale score at 8 weeks compared with placebo (35.3 with reboxetine v 27.2 with placebo; P < 0.05). The fourth subsequent RCT compared three interventions: escitalopram (10 mg/day for the first 4 weeks increasing to 20 mg/day at week 4 or week 6 if response was unsatisfactory or if there was an aggravation of the depression), citalopram (20 mg/day for the first 4 weeks increasing to 40 mg/day at week 4 or week 6 if response was unsatisfactory or if there was an aggravation of the depression) and placebo for 8 weeks. It found that escitalopram significantly improved depressive symptoms compared with placebo at 8 weeks (1 RCT, 468 people aged 18–65 years in primary care, baseline MADRS score between 22 and 40; change in MADRS total score from baseline: –15.0 points with escitalopram v –13.6 points with citalopram v –12.1 with placebo; P = 0.002 for escitalopram v placebo; other comparisons reported as not significant). The fifth subsequent RCT compared four interventions: escitalopram 10 or 20 mg daily fixed dose, citalopram 40 mg daily fixed dose, and placebo for 8 weeks. The RCT found that all active treatments significantly improved depressive symptoms compared with placebo at 8 weeks (491 outpatients aged 18–65 years, minimum baseline MADRS score of 22 and minimum baseline score of 2 on item 1 of the HAM-D at baseline; change in MADRS total score from baseline: –12.8 with escitalopram 10 mg/day v –13.9 escitalopram 20 mg/day v –12.0 with citalopram v –9.4 with placebo; P ≤ 0.05 for all treatments versus placebo). There were no significant differences in response rate between each of the escitalopram doses and the citalopram group (results presented graphically). The sixth subsequent RCT compared pindolol (2.5 mg 3 times daily) plus milnacipran (50 mg twice daily) versus placebo plus milnacipran (50 mg twice daily) for 6 weeks. It found that pindolol plus milnacipran significantly improved depressive symptoms compared with placebo plus milnacipran at day 7 (1 RCT, 78 inpatients or outpatients, aged 18–70 years in primary care, minimum baseline MADRS score of ≥ 18; change in MADRS total score from baseline: –9.6 with pindolol plus milnacipran v –5.3 with milnacipran plus placebo; P = 0.03; difference at other time points reported as significant). The seventh subsequent RCT compared duloxetine (60 mg/day once daily; if necessary the dose could be reduced to 40 mg/day, but had to be escalated back to 60 mg/day after 3 weeks) versus placebo for 9 weeks. It found that duloxetine significantly improved depressive symptoms compared with placebo (245 people aged > 18 years, minimum baseline HAM-D-17 [17-item Hamilton Depression Rating Scale] score of 15 and CGI-S score of 4; change in HAM-D-17 from baseline: –10.9 with duloxetine v –6.1 with placebo; P < 0.001). The RCT also found that duloxetine significantly improved probability of response and remission (estimated response: 62% with duloxetine v 29% with placebo; P < 0.001; estimated remission: 44% with duloxetine v 16% with placebo; P < 0.001, no further details reported).

In older adults:

We found one systematic review and two subsequent RCTs which compared antidepressant drugs versus placebo. The review found that TCAs, SSRIs, or MAOIs significantly reduced the proportion of people who failed to recover over 4–7 weeks compared with placebo (search date 2000, 17 RCTs, 1326 people aged > 55 years, with mild to moderate or severe depression; numbers failing to recover: 125/245 [51%] with TCAs v 167/223 [75%] with placebo: RR 0.68, 95% CI 0.59 to 0.78, NNT 4, 95% CI 4 to 5; 261/365 [72%] with SSRIs v 310/372 [83%] with placebo: RR 0.86, 95% CI 0.79 to 0.93, NNT 9, 95% CI 9 to 10; 34/58 [59%] with MAOIs v 57/63 [90%] with placebo: RR 0.64, 95% CI 0.50 to 0.81, NNT 4, 95% CI 3 to 4). The first subsequent RCT compared controlled release paroxetine (≤ 50 mg/day) versus immediate release paroxetine (≤ 40 mg/day) versus placebo. It found that both preparations of paroxetine significantly increased the proportion of people who responded (defined as HAM-D < 8) compared with usual care after 12 weeks (319 people, mean age 70 years, HAM-D > 17; proportion responding: 43% with controlled release paroxetine v 44% with immediate release paroxetine v 26% with placebo; P = 0.009 for controlled release paroxetine v placebo, P = 0.01 for immediate release paroxetine v placebo). The second subsequent RCT compared sertraline 50 or 100 mg versus placebo. It found that sertraline significantly increased the proportion of people who responded (defined as CGI score of 1 or 2) versus placebo after 8 weeks (747 people aged ≥ 60 years; proportion responding: 45% with sertraline v 35% with placebo; P = 0.005).

Psychotic depression:

We found one systematic review (search date 2004, 10 RCTs, 548 people) that compared the effectiveness of drug treatments for people with psychotic depression. The review found no significant difference for treatment of psychotic depression with amitriptyline compared with placebo (1 RCT, RR 8.40, 95% CI 0.50 to 147.87, P = 0.14).

Atypical depression:

We found one systematic review (search date 2004, 8 RCTs, 792 people with atypical depression) which compared the clinical effectiveness of drug treatments. The review found that MAOIs significantly improved atypical depression compared with placebo (4 RCTs, 250 people, mean effect size: 0.45, 95% CI 0.35 to 0.60). However, this review found an asymmetrical distribution for comparisons between MAOIs and placebo, possibly owing to one study that showed a very high response rate difference between phenelzine and placebo (25/30 [83%] with phenelzine v 5/26 [19%] with placebo). It must be noted that this high response rate difference does not correlate with a relatively large sample size. Furthermore, this finding is in contrast to the lower response rate differences in the other three studies comparing the efficacy of MAOIs and placebo in people suffering from atypical depression (first study: 24/34 [71%] with phenelzine v 13/47 [28%] with placebo; second study: 12/17 [71%] with phenelzine v 7/24 [29%] with placebo; third study: 21/36 [58%] with phenelzine v 10/36 [28%] with placebo).

Harms

There is concern that antidepressant drugs (especially SSRIs) may increase the risk of self harm and suicide. Recently a matched case control study was carried out to estimate the relative risk of suicide attempt and suicide death in severely depressed children and adults treated with antidepressant drugs compared with those not treated with antidepressant drugs. Medicaid beneficiaries from all 50 US states who received inpatient treatment for depression, excluding people treated for pregnancy, bipolar disorder, schizophrenia or other psychoses, mental retardation, dementia, or delirium were included. Controls were matched to cases for age, sex, race or ethnicity, state of residence, substance use disorder, recent suicide attempt, number of days since hospital discharge, and recent treatment with antipsychotic, anxiolytic/hypnotic, mood stabiliser, and stimulant medications. The main outcome measures were suicide attempts and suicide deaths. In adults (aged 19–64 years), antidepressant drug treatment was not significantly associated with suicide attempts (OR 1.10, 95% CI 0.86 to 1.39 [521 cases and 2394 controls]) or suicide deaths (OR 0.90, 95% CI 0.52 to 1.55 [86 cases and 396 controls]). However, in children and adolescents (aged 6–18 years), antidepressant drug treatment was significantly associated with suicide attempts (OR 1.52, 95% CI 1.12 to 2.07 [263 cases and 1241 controls]) and suicide deaths (OR 15.62, 95% CI 1.65 to infinity [8 cases and 39 controls]). In these high risk people, antidepressant drug treatment does not seem related to suicide attempts and death in adults, but might be related in children and adolescents. These findings support careful clinical monitoring during antidepressant drug treatment of severely depressed young people. Regulatory authorities in Europe, the UK, and the USA have issued warnings about the use of SSRIs in children and adolescents. The European Medicines Agency (EMEA) has ruled that SSRIs and selective serotonin and norepinephrine reuptake inhibitors should not be prescribed for depression for children and adolescents under the age of 18 years. The Committee for the Safety of Medicines in the UK has advised that the balance of risks and benefits for the treatment of depression in the paediatric population is unfavourable for paroxetine, citalopram, sertraline, venlafaxine, escitalopram, and mirtazapine. The regulatory authority in the USA requires a safety warning in bold text about suicide risk in package inserts for all antidepressants. National Institute for Health and Clinical Excellence (NICE) guidelines for the management of depression in primary and secondary care recommend prescription of SSRIs in routine care. There is limited robust evidence available to examine the link between SSRIs and increased risk of self harm or suicide in adults and, in light of this, practitioners should be guided by the recommendations and warnings issued by their national drug regulatory authorities with respect to the prescribing of antidepressants, particularly in children and adolescents (see review on depression in children and adolescents). The first review gave no information on adverse effects. The second review found that people taking low dose TCAs were 111% (95% CI 35% to 228%) more likely than people taking placebo to withdraw because of adverse effects. However, it found no significant difference between low dose TCAs and placebo in the proportion of people who withdrew for any cause (RR 1.08, 95% CI 0.93 to 1.26). People taking low dose TCAs were 63% (95% CI 36% to 95%) more likely to experience at least one adverse effect than people taking placebo. The third review found that significantly more people taking SSRIs than placebo withdrew because of adverse effects (ARI 5.5%, 95% CI 3.4% to 7.6%). The review gave no information on adverse effects of MAOIs, TCAs, or venlafaxine compared with placebo. The fourth review found that, compared with placebo, TCAs significantly increased the proportion of people who had constipation, dizziness, and dry mouth (constipation: 2 RCTs, 78/239 [33%] with TCAs v 27/244 [11%] with placebo; RR 2.95, 95% CI 1.97 to 4.41; dizziness: 59/239 [25%] with TCAs v 32/244 [13%] with placebo; RR 1.89, 95% CI 1.28 to 2.79; dry mouth: 163/239 [68%] with TCAs v 45/244 [18%] with placebo; RR 3.70, 95% CI 2.80 to 4.88). It found that, compared with placebo, SSRIs significantly increased the proportion of people who had sweating, sexual dysfunction, insomnia, and dry mouth (sweating: 2 RCTs, 41/311 [13%] with SSRIs v 12/308 [4%] with placebo; RR 3.40, 95% CI 1.81 to 6.36; sexual dysfunction: 22/153 [14%] with SSRIs v 9/156 [6%] with placebo; RR 2.49, 95% CI 1.18 to 5.23; insomnia: 68/292 [23%] with SSRIs v 48/292 [16%] with placebo; RR 1.42, 95% CI 1.02 to 1.98; dry mouth: 52/292 [18%] with SSRIs v 34/292 [12%] with placebo; RR 1.56, 95% CI 1.05 to 2.31). The review found insufficient evidence from one RCT to compare the adverse effects of MAOIs versus placebo. The fifth review found no differences in tolerability or adverse events between SSRIs plus pindolol compared with SSRIs plus placebo (tolerability: OR 1.3, 95% CI 0.8 to 2.3, adverse events: OR 1.3, 95% CI 0.7 to 2.1). Small sample size may limit these findings. The final review found that people taking either TCAs or SSRIs were significantly more likely than people taking placebo to withdraw because of adverse effects (81/692 [12%] with TCAs v 30/578 [5%] with placebo; RR 2.35, 95% CI 1.59 to 3.46; 15/573 [3%] with SSRIs v 15/573 [3%] with placebo; RR 2.01, 95% CI 1.10 to 3.70). The first subsequent RCT found that, compared with placebo, more people taking reboxetine had dry mouth, blurred vision, constipation, vomiting, tremor, hypotension, decreased appetite, and sexual disturbance (dry mouth: 16/28 [57%] with reboxetine v 6/28 [21%] with placebo; insomnia: 7/28 [25%] with reboxetine v 0/28 [0%] with placebo; blurred vision: 5/28 [18%] with reboxetine v 1/28 [4%] with placebo; sweating: 5/28 [18%] with reboxetine v 0/28 [0%] with placebo; constipation: 4/28 [14%] with reboxetine v 2/28 [7%] with placebo; vomiting: 4/28 [14%] with reboxetine v 1/28 [4%] with placebo; tremor: 4/28 [14%] with reboxetine v 3/28 [11%] with placebo; hypotension: 3/28 [11%] with reboxetine v 0/28 [0%] with placebo; decreased appetite: 3/28 [11%] with reboxetine v 0/28 [0%] with placebo; sexual disturbance: 3/28 [11%] with reboxetine v 1/28 [4%] with placebo; CI not reported for any outcome). Fewer people had headache (2/28 [7%] with reboxetine v 5/28 [18%] with placebo; CI not reported). The second subsequent RCT found that, compared with placebo, significantly more people taking reboxetine had urinary hesitancy (11% with reboxetine v 1% with placebo; reported as significant, CI not reported). The third subsequent RCT gave no information on adverse effects. The fourth subsequent RCT reported no significant difference between groups in adverse events or numbers who withdrew because of adverse events (adverse events: 59.7% with placebo v 69.7% with escitalopram v 65.0% with citalopram; withdrawals caused by adverse events: 2.6% with placebo v 2.6% with escitalopram v 3.8% with citalopram; comparisons reported as not significant). The fifth subsequent RCT reported that significantly more people withdrew from the study because of adverse events in the escitalopram 20 mg daily and citalopram 40 mg daily groups compared with placebo or with low dose escitalopram 10 mg daily (withdrawals caused by adverse events: 2.5% with placebo v 4.2% with escitalopram 10 mg/day v 10.4% with escitalopram 20 mg/day v 8.8% with citalopram; P ≤ 0.05 for escitalopram 20 mg/day and citalopram v placebo). It also found that the rate of adverse events was significantly greater than placebo for high dose escitalopram 20 mg daily and citalopram (70.5% with placebo v 85.6% with escitalopram v 86.4% with citalopram; P < 0.01 for both comparisons). The sixth subsequent RCT reported no significant differences in adverse events between the pindolol plus milnacipran and the placebo plus milnacipran groups. The seventh subsequent RCT reported that significantly more people in the duloxetine group experienced adverse events (nausea: 57/123 [46%] with duloxetine v 11/122 [9%] with placebo; dry mouth: 34/123 [28%] with duloxetine v 8/122 [7%]; somnolence: 26/123 [21%] with duloxetine v 6/122 [5%] with placebo; diarrhoea: 23/123 [19%] with duloxetine v 8/122 [7%] with placebo; anorexia: 16/123 [13%] with duloxetine v 2/122 [2%] with placebo; constipation: 16/123 [13%] with duloxetine v 2/122 [2%] with placebo; vomiting: 13/123 [11%] with duloxetine v 2/122 [2%] with placebo). Treatment with duloxetine significantly increased weight loss compared with placebo (mean weight change: –0.76 kg with duloxetine v +0.21 kg with placebo; P = 0.005).

In older adults:

The systematic review did not report data on adverse events. The first subsequent RCT found a greater proportion of people withdrew because of adverse events with both controlled and immediate release paroxetine compared with placebo (proportion withdrawing: 12.5% with controlled release paroxetine v 16.0% with immediate release paroxetine v 8.3% with placebo; significance not reported). The RCT reported that the most common adverse events after treatment with paroxetine included somnolence, dry mouth, headache, diarrhoea, nausea, and decreased appetite (no further data reported). The second subsequent RCT reported that sertraline significantly increased diarrhoea, headache, nausea, somnolence, insomnia, tremor, and fatigue (P < 0.05 for each comparison). There was a greater number of treatment emergent adverse events after treatment with sertraline compared with placebo (53/371 [14%] with sertraline v 18/376 [5%] with placebo; significance not reported).

Psychotic depression:

The systematic review gave no information on adverse effects.

Atypical depression:

The systematic review gave no information on adverse effects.

Comment

Many of the RCTs were sponsored by the drug manufacturer, and sponsorship has been suggested as a potential factor influencing the outcomes of RCTs. Evidence of publication bias has been found in the RCTs of SSRIs, and the efficacy and safety of these drugs is currently under review by the regulatory authorities in several countries. For mild to moderate depression, most RCTs were short term and focused exclusively on improvement in depressive symptoms. Longer term RCTs that could provide more data on the sustainability of benefits and the potential adverse effects are lacking. Although effects on depressive symptoms are clear, effects on functional status and health related quality of life outcomes are not well described. Most RCTs analysed results using “last observation carried forward”: this method may bias the estimate of treatment efficacy. A “pure” intention to treat analysis, following participants for the whole trial duration even if they withdraw, would be more conservative and would replicate what happens in clinical practice. The first review found that results were sensitive to the diagnostic criteria used; the mean effect size for antidepressant drugs was 0.5 in those RCTs in which depressive disorders were diagnosed according to standard criteria (mainly Diagnostic and statistical manual of mental disorders, 3rd edition, revised [DSM-III-R]) and 0.4 in those RCTs that did not use objective diagnostic criteria. The third review forms part of a larger review of 315 RCTs in people with depression, and we were unable to obtain the full reference list; it is therefore unclear whether it contains RCTs assessed in the other reviews. In the fifth review, the definition of clinical response varied betweens studies, with some reporting more than one criterion.

In older adults:

The review comparing antidepressant drugs versus placebo in older people was limited by the diversity of populations included and by the brevity of the RCTs. The reviewers recommended at least 6 weeks of antidepressant treatment in elderly people to achieve optimal effect. Metabolic and physical changes with age mean that older people may be more prone to adverse effects such as falls. Because older people often take more medications, they may be at greater risk of drug interactions.

Clinical guide:

The concept of atypical depression as a distinct subtype is based on reported preferential response to one class of antidepressants — MAOIs. The preferential response of atypical depression to MAOIs is now part of accepted wisdom in clinical psychiatry, even though the use of varying definitions of atypical depression before the inclusion of operational criteria in Diagnostic and statistical manual of mental disorders (DSM-IV) makes it difficult to rely only on these findings.

Substantive changes

Prescription antidepressants versus placebo Four systematic reviews added. Categorisation unchanged (Beneficial) but benefits and harms sections enhanced.

BMJ Clin Evid. 2007 Jun 15;2007:1003.

Selective serotonin reuptake inhibitors versus each other and other prescription antidepressant drugs

Summary

One systematic review found that selective serotonin reuptake inhibitors as a class were less effective than venlafaxine in increasing the proportion of people who responded, and that sertraline could be more effective than fluoxetine in terms of response rate. RCTs in people with major depression found similar response rates at 6 weeks between fluoxetine, sertraline, and reboxetine. One systematic review found no statistically significant differences in terms of overall efficacy between mirtazapine and selective serotonin reuptake inhibitors. One systematic review found that selective serotonin reuptake inhibitors were associated with fewer adverse effects than tricyclic antidepressants, but the difference was small. Two systematic reviews, one retrospective cohort study, and two case control studies found contradictory evidence about the risk of suicide in adults treated with selective serotonin reuptake inhibitors. One of the systematic reviews and the case control studies reported no significant difference in risk of suicide between selective serotonin reuptake inhibitors and tricyclic antidepressants. One RCT and observational data suggested that abrupt withdrawal of selective serotonin reuptake inhibitors was associated with symptoms including dizziness and rhinitis, and that these symptoms were more likely with drugs with a short half life, such as paroxetine. There is evidence of publication bias in trials of selective serotonin reuptake inhibitors. Current evidence indicates no clear relationship between selective serotonin reuptake inhibitors and increased risk for suicide in adults, but selective serotonin reuptake inhibitors and tricyclic antidepressants may induce or worsen suicidal ideation and behaviour during the early phases of treatment. This may be because of increased agitation and activation. In children and adolescents, selective serotonin reuptake inhibitors generally increase adverse events compared with placebo, and the safety of these drugs is currently under review by regulatory authorities in several countries.

Benefits

Selective serotonin reuptake inhibitors versus each other:

We found two systematic reviews comparing selective reuptake inhibitors (SSRIs) with other SSRIs to treat major depressive disorder. The first review (search date 2005, 26 RCTs) evaluated data on the commonly prescribed SSRIs for treatment of major depressive disorder. Overall, the RCTs included in the review found similar outcomes among the six SSRIs (fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, and escitalopram); 20 RCTs reported no statistically significant differences in any efficacy measure at study end. One RCT comparing escitalopram with citalopram found that escitalopram was significantly more effective for treating major depressive disorder compared with citalopram (≥ 50% improvement in total score on the Montgomery–Asberg Depression Rating Scale (MADRS): 64% with escitalopram v 53% with citalopram; P = 0.021, no further data reported). By contrast, a similarly designed RCT did not find statistically significant differences between escitalopram and citalopram. The review compared paroxetine with fluoxetine (8 RCTs, 744 people) and found that paroxetine was not significantly more effective than fluoxetine for treatment of major depressive disorder (HAM-D scale relative benefit 1.09, 95% CI, 0.97 to 1.21). However, one RCT of 6 weeks' duration (108 older people, 87% women, mean age 74 years) found that paroxetine was significantly more effective than fluoxetine for treating major depressive disorder (≥ 50% improvement in HAM-D total score: 38% with paroxetine v 17% with fluoxetine; P < 0.05). The review also compared fluoxetine with sertraline (5 RCTs, 1190 people). Although no individual RCT found a statistically significant result, pooled data suggested a modest additional treatment effect (relative benefit 1.10, 95% CI 1.01 to 1.22) for sertraline compared with fluoxetine. It is not infrequent for RCTs to find contrasting evidence in this field. Trials reporting significant differences are frequently funded by pharmaceutical companies, and the company's drug is usually favoured over the comparator. However, it is very difficult to determine whether the statistically non-significant findings are consistently related to quality ratings, trial duration, sample size, or non-inferiority design. The second systematic review (search date 2004) compared fluoxetine with other SSRIs. The review found no significant difference between fluoxetine compared with fluvoxamine for treatment of depression (1 RCT, 177 people, failure to respond: 54/91 [59%] with fluoxetine v 52/86 [60%] with fluvoxamine; OR 0.95, 95% CI 0.52 to 1.74). However, the review also found that both paroxetine and sertraline were significantly more effective compared with fluoxetine for treatment of depression (paroxetine: 8 RCTs, 960 people, failure to respond: 198/481 [41%] with fluoxetine v 175/479 [36%] with paroxetine; OR, 1.25, 95% CI 0.96 to 1.63; sertraline: 7 RCTs, 1266 people; failure to respond: 298/625 [48%] with fluoxetine v 255/641 [40%] with sertraline; OR 1.40, 95% CI 1.11 to 1.76).

Selective serotonin reuptake inhibitors versus tricyclic antidepressants:

We found five systematic reviews and one subsequent RCT in people with mild to moderate or severe depression comparing SSRIs versus tricyclic antidepressants (TCAs). The reviews found no significant difference in overall effectiveness between TCAs and SSRIs. The first review (search date 1999, 63 RCTs, 6767 people) found no significant difference in overall symptoms between SSRIs and TCAs (mean effect size +0.03, 95% CI –0.02 to +0.09). The second review (search date 1997, 95 RCTs, 10 533 people aged 18–80 years) found that SSRIs may be slightly more acceptable overall than TCAs, as measured by the proportion of people who withdrew from clinical trials for any cause (RR of withdrawal 0.88, 95% CI 0.83 to 0.93; NNH 26, 95% CI 18 to 46). The third review (search date 1998, 150 RCTs, ≥ 16 000 people with major depression; see comment below) compared newer antidepressants (SSRIs [43 RCTs], monoamine oxidase inhibitors, and venlafaxine) versus TCAs for at least 6 weeks. Response was defined as a 50% reduction in depression rating scale score or a Clinical Global Impression Scale (CGI) score of 1 (very much improved) or 2 (much improved). The review found no significant difference between newer antidepressants and TCAs in the proportion of people who responded (54% with newer antidepressants v 54% with placebo; RR 1.00, 95% CI 0.97 to 1.06). The results were similar when the analysis was restricted to RCTs conducted in primary care. The fourth review (search date 2000, 45 RCTs, 5640 people) compared SSRIs with amitriptyline. The review found no significant differences on a dichotomous outcome in treatment of depression in either an inpatient (5 RCTs, OR 1.30, 95% CI 0.87 to 1.96) or outpatient (10 RCTs, OR 1.08, 95% CI 0.86 to 1.35) population between SSRIs and amitriptyline. Similarly, on a continuous outcome, there were no statistically significant differences between amitriptyline and SSRIs, either for inpatients (7 RCTs, SMD +0.34, 95% CI –0.03 to +0.72) or for outpatients (15 RCTs, SMD +0.08, 95% CI –0.05 to +0.20). The fifth review (search date 2004) compared fluoxetine versus TCAs including amitriptyline, clomipramine, desipramine, dosulepin (dothiepin), doxepin, imipramine and lofepramine. The review defined response rate as the number of people showing a reduction of at least 50% at the Hamilton Depression Scale (HDRS). The review found no significant difference between fluoxetine compared with TCAs as a class for treatment of depression (failure to respond: 481/1008 [48%] with fluoxetine v 504/1032 [49%] with TCAs; OR 0.95, 95% CI 0.80 to 1.14, P = 0.6). However, in head to head comparisons, only dosulepin was found to be significantly more effective than fluoxetine (2 RCTs, 144 people, failure to respond: 42/72 [58%] with fluoxetine v 29/72 [40%] with dosulepin; OR 2.09, 95% CI 1.08 to 4.05).

Selective serotonin reuptake inhibitors versus monoamine oxidase inhibitors:

We found one systematic review (search date 2004) which compared the clinical effectiveness of drug treatments for people with atypical depression (defining atypical depression as a depressive subtype that is preferentially responsive to MAOI treatment). The review found that MAOIs (phenelzine and moclobemide) were not significantly more effective for treatment of atypical depression in terms of response rate and treatment effect size (response rate, 3 RCTs, 265 people: 85/127 [67%] with MAOIs v 90/138 [65%] with SSRIs; treatment effect size, 3 RCTs, 265 people: +0.02, 95% CI –0.10 to +0.14) compared with SSRIs.

Selective serotonin reuptake inhibitors versus venlafaxine:

See benefits of venlafaxine.

Selective serotonin reuptake inhibitors versus reboxetine:

See benefits of reboxetine.

Selective serotonin reuptake inhibitors versus mirtazapine:

We found one systematic review (search date 2005, 4 RCTs, 1007 people) which compared SSRIs (sertraline [1 RCT, 346 people], paroxetine [2 RCTs, 529 people], and fluoxetine [1 RCT, 132 people]) with mirtazapine. The review found no significant differences between SSRIs and mirtazapine in overall efficacy and response rates (no data reported). Mirtazapine consistently had a faster onset of action than fluoxetine, sertraline, or paroxetine, and one RCT found that sleep quality was better among people treated with mirtazapine, however, this outcome was not reported, and probably not assessed, in other RCTs (no further data reported).

Selective serotonin reuptake inhibitors plus benzodiazepines versus selective serotonin reuptake inhibitors alone:

We found no systematic review, but found one RCT. The RCT compared fluoxetine 20–40 mg daily plus clonazepam 0.5–1.0 mg daily for 18 weeks versus fluoxetine plus placebo. It found no significant difference between fluoxetine plus clonazepam and fluoxetine alone in the proportion of people who responded at 6 weeks (50 people aged 18–70 years with moderate to severe depression for at least 1 month and a HAM-D score of 18–26; response defined as CGI score of 1 [very much improved] or 2 [much improved]: 76% with fluoxetine plus clonazepam v 56% with fluoxetine alone; reported as not significant, CI not reported). The RCT is likely to have been underpowered to detect a clinically important difference in outcomes.

Psychotic depression:

We found one systematic review (search date 2004, 3 RCTs, 101 people with psychotic depression), which compared SSRIs with each other or other antidepressants. The first RCT included in the review found that imipramine was significantly more effective than fluvoxamine for treating psychotic depression (1 RCT, 48 people: 16/25 [64%] with imipramine v 7/23 [30%] with fluvoxamine; RR 2.10, 95% CI 1.06 to 4.17, P = 0.03). The second RCT included in the review found that sertraline was significantly more effective than paroxetine (1 RCT, 32 people: 13/18 [72%] with sertraline v 3/14 [21%] with paroxetine; RR 3.37, 95% CI 1.19 to 9.57, P = 0.02). The third RCT included in the review found no significant difference between fluvoxamine and venlafaxine for treatment of psychotic depression (1 RCT, 22 people: 9/11 [82%] with fluvoxamine v 6/11 [55%] with venlafaxine; RR 1.50, 95% 0.82 to 2.75, P = 0.2).

Harms

Common adverse events with selective serotonin reuptake inhibitors versus tricyclic antidepressants:

One systematic review (search date 1996) compared adverse events with SSRIs versus TCAs in people aged 18 years or over with all severities of depression (see table 1 ). It found that about twice as many people taking TCAs compared with SSRIs had dry mouth, constipation, and dizziness, but that slightly more people taking SSRIs had nausea, diarrhoea, anxiety, agitation, insomnia, nervousness, and headache. Another systematic review (search date 2000) compared treatment discontinuation rates with amitriptyline versus SSRIs in people aged 18 years or over with depression. Amitriptyline was less well tolerated than SSRIs in outpatients (OR 0.77, 95% CI 0.67 to 0.89; 27 RCTs, 4015 people); no statistically significant differences were found in inpatients (OR 0.99, 95% CI 0.78 to 1.24; 15 RCTs, 1376 people). One subsequent systematic review (search date 2004) comparing fluoxetine versus all other antidepressants found that, in terms of people who withdrew during the trial for any cause, fluoxetine was better tolerated than TCAs (OR 0.78, 95% CI 0.68 to 0.89). In particular, fluoxetine was better tolerated than amitriptyline (OR 0.64, 95% CI 0.47 to 0.85) and imipramine (OR 0.79, 95% CI 0.63 to 0.99). An advantage in terms of tolerability, although not statistically significant, was found in favour of fluoxetine over lofepramine (OR 0.51, 95% CI 0.25 to 1.03) and nortriptyline (OR 0.68, 95% CI 0.45 to 1.03); by contrast, dosulepin was better tolerated than fluoxetine (OR 1.44, 95% CI 0.98 to 2.12). In terms of adverse effect profile, data from 26 RCTs included in the previous systematic review showed that 50.9% of people treated with fluoxetine experienced adverse effects during the study compared with 60.3% of people who received a TCA (RR 0.84, 95% CI 0.76 to 0.94). However, the analysis of individual TCAs showed that relative risk for adverse effects significantly favoured fluoxetine compared with amitriptyline and clomipramine, but not compared with the other TCAs included in the analysis. In this review significant differences were reported as numbers needed to treat (positive NNTs indicating a significant advantage for fluoxetine, negative NNTs indicating a significant advantage for comparison). TCAs were associated with less insomnia, anxiety, nausea, anorexia, and weight loss than fluoxetine (insomnia, 65 RCTs: NNT –33, 95% CI –24 to –52; anxiety, 65 RCTs: NNT –105, 95% CI –55 to –1000; nausea, 65 RCTs: NNT –13, 95% CI –10 to –16; anorexia, 65 RCTs: NNT –100, 95% CI –56 to –434; weight loss, 6 RCTs: NNT –23, 95% CI –14 to –55). TCAs were associated with more sedation, dizziness, dry mouth, blurred vision, constipation, and weight gain than fluoxetine (sedation, 65 RCTs: NNT 21, 95% CI 16 to 30; dizziness, 10 RCTs: NNT 13, 95% CI 10 to 18; dry mouth, 10 RCTs: NNT 25, 95% CI 17 to 53; blurred vision, 65 RCTs: NNT 100, 95% CI 51 to 666; constipation, 65 RCTs: NNT 12, 95% CI 10 to 14; weight gain, 65 RCTs: NNT 39, 95% CI 30 to 59).

Table 1.

Adverse events (% of people) with selective serotonin reuptake inhibitors versus tricyclic antidepressant drugs (see text).

Adverse effects SSRI event rates (%) TCA event rates (%)
Dry mouth 21 55
Constipation 10 22
Dizziness 13 23
Nausea 22 12
Diarrhoea 13 5
Anxiety 13 7
Agitation 14 8
Insomnia 12 7
Nervousness 15 11
Headache 17 14
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SSRI, selective serotonin reuptake inhibitors; TCA, tricyclic antidepressants.

Adverse effects with different selective serotonin reuptake inhibitors:

The overall incidence of adverse events is similar among antidepressants: discontinuation rates attributed to adverse events are similar, but available evidence suggests that the profiles of adverse effects differed among drugs. One systematic review reported the mean incidence and 95% confidence intervals for specific adverse events that were commonly reported in included RCTs (mean incidence: citalopram: diarrhoea: 6.8, 95% CI 1.8 to 11.8; headache: 5, 95% CI 0 to 24.1; insomnia: 6.4, 95% CI 1.6 to 11.2; nausea: 11.9, 95% CI 0 to 24.8; escitalopram: diarrhoea: 8.9, 95% CI 1.6 to 16.1; headache: 14.1, 95% CI 0 to 29.9; insomnia: 8.7, 95% CI 1.3 to 16.2; nausea: 14.8, 95% CI 6.1 to 23.5; fluoxetine: diarrhoea: 11.7, 95% CI 6.8 to 16.6; dizziness: 7.2, 95% CI 4.3 to 10.0; headache: 16.6, 95% CI 10.2 to 23.0; insomnia: 13.7, 95% CI 10.0 to 17.4; nausea: 18.6, 95% CI 15.1 to 22.1; fluvoxamine: headache: 14.5, 95% CI 0 to 41.5; nausea: 22.2, 95% CI 0 to 46.8; paroxetine: diarrhoea: 9.2, 95% CI 5.6 to 12.9; dizziness: 10.6, 95% CI 7.5 to 13.7; headache: 21.2, 95% CI 11.1 to 31.3; insomnia: 14.3, 95% CI 8.6 to 20.1; nausea: 18.3, 95% CI 11.1 to 25.6; sertraline: diarrhoea: 15.4, 95% CI 10.2 to 20.6; dizziness: 7.5, 95% CI 4.6 to 10.4; headache: 20.2, 95% CI 12.8 to 27.6; insomnia: 15.0, 95% CI 8.7 to 21.3; nausea: 19.5, 95% CI 14.4 to 24.6). The method and extent of assessment of adverse events varied among studies, and the pooled incidence should be interpreted with caution. One systematic review, which compared fluoxetine versus all other antidepressants, found that fluoxetine was associated with less constipation (8 RCTs, NNT 42, 95% CI 24 to 141), but more sweating (8 RCTs, NNT –58, 95% CI –32 to –400) and weight loss (4 RCTs, NNT –15, 95% CI –9 to –38) than paroxetine, and more nausea than fluvoxamine (1 RCT, NNT –5, 95% CI –2 to –71). One large cohort study of people receiving four different SSRIs (fluvoxamine [983 people], fluoxetine [692 people], sertraline [734 people], and paroxetine [13 741 people]) in primary care in the UK found that reports of common adverse events (nausea/vomiting, malaise/lassitude, dizziness, and headache/migraine) varied between SSRIs (fluvoxamine 78/1000 participant months; fluoxetine 23/1000 participant months; RR v fluvoxamine 0.29, 95% CI 0.27 to 0.32; paroxetine 28/1000 participant months; RR v fluvoxamine 0.35, 95% CI 0.33 to 0.37; sertraline 21/1000 participant months; RR v fluvoxamine 0.26, 95% CI 0.25 to 0.28). Only 52% of people responded to the questionnaire, although this response rate was similar for all four drugs. A study of spontaneous reports to the UK Committee on Safety of Medicines found similar safety profiles among the same four SSRIs.

Withdrawal effects with selective serotonin reuptake inhibitors:

We found one RCT in people aged 18 years or over (mean 30–40 years) comparing abrupt discontinuation of fluoxetine (96 people) versus continued treatment (299 people) in people who had been taking the drug for 12 weeks. It found that abrupt discontinuation was associated with increased dizziness, dysmenorrhoea, rhinitis, and somnolence (dizziness: 7% with abrupt discontinuation v 1% with continued treatment; dysmenorrhoea: 3% with abrupt discontinuation v 0% with continued treatment; rhinitis: 10% with abrupt discontinuation v 3% with continued treatment; somnolence: 4% with abrupt discontinuation v 0% with continued treatment). However, there was a high withdrawal rate in this RCT because of the return of symptoms of depression (39%), so these may be underestimates of the true rate of withdrawal symptoms. Between 1987 and 1995 the rate of spontaneous reports of suspected withdrawal reactions per million defined daily doses to the World Health Organization Collaborating Centre for International Drug Monitoring was higher for paroxetine than for sertraline and fluoxetine. The most common withdrawal effects were dizziness, nausea, paraesthesia, headache, and vertigo.

Selective serotonin reuptake inhibitors versus monoamine oxidase inhibitors:

The review gave no information on adverse effects.

Adverse events with selective serotonin reuptake inhibitors versus venlafaxine:

See harms of venlafaxine.

Selective serotonin reuptake inhibitors versus reboxetine:

See harms of reboxetine.

Selective serotonin reuptake inhibitors versus mirtazapine:

The systematic review reported that multiple trials provided some evidence that paroxetine, sertraline, and mirtazapine tended to have higher rates of sexual adverse effects than did other antidepressants (no further data reported). Of trials that reported changes in body weight, those of mirtazapine, paroxetine, fluoxetine, and sertraline differed in the percentage of people who reported such changes. On average, the most consistent percentage of people who reported weight gain were taking mirtazapine; these people had an estimated increase in body weight of 2 kg over 8 weeks. In the trials of SSRIs that reported changes in body weight, the percentage of people who reported weight gain was highest in the paroxetine group and lowest in the fluoxetine group; however, it was not possible to estimate specific changes in weight on the basis of data reported in the papers. The same review reported for mirtazapine the mean incidence and 95% confidence intervals for specific adverse events that were commonly reported in other included RCTs (mean incidence, diarrhoea: 8.8, 95% CI 0 to 22.4; dizziness: 12.0, 95% CI 2.9 to 21.2; headache: 12.1, 95% CI 6.3 to 17.9; insomnia: 8, 95% CI 0 to 49.2; nausea: 4.3, 95% CI 0 to 8.9).

Adverse events with selective serotonin reuptake inhibitors plus benzodiazepines:

The RCT found that 30% of people taking fluoxetine plus clonazepam had decreased appetite. It also found that 28% of people taking fluoxetine alone had headache and 24% had sleep disturbance.

Psychotic depression:

The systematic review gave no information on adverse effects.

Selective serotonin reuptake inhibitors during pregnancy:

We found one systematic review (search 2004). All SSRIs, as well as venlafaxine, have been found to cross the placenta. Recently, the US Food and Drug Administration (FDA) has determined that exposure to paroxetine in the first trimester of pregnancy may increase the risk for congenital malformations, particularly cardiac malformations. At the request of the FDA, the manufacturer has changed the pregnancy category of paroxetine from C to D and added new data and recommendations to the Warnings section of the prescribing information of paroxetine. The FDA is awaiting the final results of the recent studies, and accruing additional data related to the use of paroxetine in pregnancy, in order to better characterise the risk for congenital malformations associated with paroxetine. The review found that paroxetine and sertraline pass through the placenta more slowly than fluoxetine, but this finding must be interpreted with caution in clinical practice. During the first trimester, the main concern is malformation of the fetus, although there is no current evidence that SSRIs or venlafaxine cause increased teratogenicity. Concerns in the third trimester focus on neonatal withdrawal, because third trimester exposure to antidepressant drugs has been correlated with higher risk of adverse effects in neonates, such as respiratory distress, feeding difficulties, and low birth weight. However, these effects have been shown to be transient. Because every mother and baby metabolise medication differently, no universal statement about the choice of a particular medication during pregnancy can be made. When a woman is treated with antidepressant drugs during pregnancy, concerns of both the mother and doctor relate to the risk of teratogenesis, neonatal toxicity, and long term effects on child development. Although there is little evidence from research, no long term adverse effects from prenatal exposure to SSRIs or venlafaxine have been reported up to now. This area requires ongoing research.

Suicide with selective serotonin reuptake inhibitors:

There remains uncertainty about the safety of SSRIs, which may cause worsening of suicidal ideas in vulnerable people. We found two recent systematic reviews which specifically considering suicide related outcomes. The first systematic review (search date 2003, 702 RCTs, 87 650 people) compared SSRIs versus either placebo or active non-SSRI controls. It found that SSRIs significantly increased the risk of fatal or non-fatal suicide attempts compared with placebo (OR 2.28, 95% CI 1.14 to 4.55, NNH 684, CI not reported). A significant increase in risk of fatal or non-fatal suicide attempt was also observed with SSRIs compared with drugs other than TCAs (OR 1.94, 95% CI 1.06 to 3.57, NNH 239, CI not reported). There was no significant difference in risk of suicide between SSRIs and TCAs (OR 0.88, 95% CI 0.54 to 1.42). RCTs were included in this review regardless of treatment condition, and 414/702 (59%) of RCTs were in people who had a diagnosis other than major depressive disorder. A second systematic review (search date 2004, 477 RCTs, 45 704 people), which also included RCTs regardless of treatment condition, compared SSRIs versus placebo. It found no evidence that SSRIs increased suicide risk (OR 0.85, 95% CI 0.20 to 3.40). The review suggested that increased risk could not be ruled out, and that RCTs with longer follow up times were required. One historical cohort study followed 172 598 people who had at least one prescription for one of 10 antidepressant drugs during the study period in general practice in the UK. It found that the risk of suicide was higher in people who received fluoxetine (19/10 000 person years, 95% CI 9/10 000 person years to 34/10 000 person years) than in those receiving dosulepin (RR of suicide v dosulepin 2.1, 95% CI 1.1 to 4.1). In a nested case controlled subgroup analysis in people with no history of suicidal behaviour or previous antidepressant prescription, the risk remained the same, although the confidence interval broadened to make the result non-significant (RR 2.1, 95% CI 0.6 to 7.9). Although the apparent association may be because of residual confounding, there remains uncertainty about the possible association between fluoxetine and suicide. However, any absolute increase in risk is unlikely to be large. One case control study (146 095 people receiving antidepressant for depression) reported no significant increase in suicide risk in people prescribed SSRIs compared with TCAs (OR for suicide 0.57, 95% CI 0.26 to 1.25). Another case control study (159 810 people) found no significant increase in suicide risk with individual SSRIs (amitriptyline, fluoxetine, paroxetine) compared with dosulepin (OR: amitriptyline: 0.83, 95% CI 0.61 to 1.13; fluoxetine: 1.16, 95% CI 0.90 to 1.50; paroxetine: 1.29, 95% CI 0.97 to 1.70). More recently, to test the hypothesis that SSRI antidepressants may have a suicide emergent effect, detections of different antidepressants in the forensic toxicological screening of 14 857 suicides were compared with those in 26 422 cases of deaths by accident or natural causes in Sweden from 1992 to 2000. In the toxicological screening, antidepressant drugs were detected in 3096 (20%) of the 14 857 cases of suicide investigated. The number of detections of various antidepressants in the cases involved was 3411, of which 48% were SSRIs, and the number of detections in the 26 422 controls was 1538. In the analysis of toxicological detections in suicides and controls, SSRIs were under-represented compared with other antidepressants (OR 0.83, 99% CI 0.77 to 0.90). The differences within the SSRIs were not significant, with the exception of fluvoxamine. The odds ratio for the TCAs as a class (including maprotiline [a tetracyclic antidepressant]) was 1.01 (99% CI 0.90 to 1.14), but it was higher for the class of newer antidepressants (moclobemide [a MAOI], mianserin [a tetracyclic antidepressant], mirtazapine [a NaSSA], reboxetine [a norepinephrine reuptake inhibitor], and venlafaxine [a serotonin and norepinephrine reuptake inhibitor]; OR 1.78, 99% CI 1.46 to 2.16). In people aged less than 15 years, among the 52 cases of suicide, seven were positive for antidepressants (clomipramine, imipramine [2 people], maprotiline, trimipramine, mianserin and venlafaxine), but no SSRIs were detected. In the 15–19 years age group, among the 326 cases of suicide, 13 were positive for antidepressants (6 with TCAs [amitriptyline, clomipramine, trimipramine], 6 with SSRIs [citalopram, fluoxetine, sertraline], 1 with mirtazapine), and SSRIs had lower relative risks in suicides compared with non-SSRIs. In this study, the hypothesis that treatment of depressed people with SSRIs leads to an increased risk of suicide was not supported by this analysis of the total suicidal outcome of the nationwide use of SSRIs in Sweden over a period of 9 years. Healthcare professionals should be encouraged to prescribe effective doses in people with moderate to severe unipolar depression. SSRIs, similarly to TCAs, may induce or worsen suicidal ideation and suicide attempts during the early phases of treatment, possibly because they cause agitation and activation during that time. During these early phases, care plans should include frequent follow up visits, and the supporting role of family members and caregivers should be considered. Given the risk of reactions to discontinuation, people should be warned against ending treatment abruptly. These indications apply to adults only. The Committee for the Safety of Medicines in the UK has advised that the balance of risks and benefits for the treatment of depression in the paediatric population is unfavourable for the SSRIs (excluding fluoxetine) and mirtazapine and venlafaxine. The regulatory authority in the USA requires a safety warning in bold text about suicide risk in package inserts for all antidepressant drugs. National Institute for Health and Clinical Excellence (NICE) guidelines for the management of depression in primary and secondary care recommend prescription of SSRIs in routine care. There is limited robust evidence available to examine the link between SSRIs and increased risk of self harm or suicide in adults and, in light of this, practitioners should be guided by the recommendations and warnings issued by their national drug regulatory authorities with respect to the prescribing of antidepressants, particularly in children and adolescents (see review on depression in children and adolescents).

Comment

The second review forms part of a larger review of 315 RCTs in people with depression, and we were unable to obtain the full reference list; it is therefore unclear whether it contains RCTs assessed in the other reviews. We found one systematic review (search date 2000, 103 RCTs) that assessed the effects of fluoxetine dose on outcomes in RCTs comparing fluoxetine versus tricyclic, heterocyclic and related antidepressants, SSRIs, and newer antidepressants in people with depression. The review found that the weighted rate of fluoxetine responders was higher in RCTs where fluoxetine was the experimental drug (70%) compared with RCTs where fluoxetine was the control drug (58%), possibly reflecting the use of higher doses of fluoxetine in RCTs where fluoxetine was the experimental drug. The review did not assess the proportion of responders with other antidepressants and did not adjust for possible confounders. See comment on prescription antidepressant drugs versus placebo.

Clinical guide:

NICE guidelines for depression recommend that, when an antidepressant is to be prescribed in routine care, it should be an SSRI, because SSRIs are as effective as TCA antidepressants and are less likely to be discontinued because of adverse effects. The choice of individual antidepressant should also be based on the tolerability profile and patient preferences. When prescribing an SSRI, consideration should be given to using a product in a generic form.

Substantive changes

Selective serotonin reuptake inhibitors and related drugs versus each other and other prescription antidepressant drugs Six systematic reviews and one retrospective study added. Benefits and harms sections enhanced.

BMJ Clin Evid. 2007 Jun 15;2007:1003.

Tricyclic antidepressants versus each other and other prescription antidepressant drugs

Summary

One systematic review found that amitriptyline was more effective in an inpatient population compared with other tricyclic antidepressants. One systematic review and one subsequent RCT found no significant difference between tricyclic antidepressants and venlafaxine in the proportion of people who responded over 1–12 months. Another systematic review suggested that tricyclic antidepressants were more effective than monoamine oxidase inhibitors in people with severe depressive disorders, but may be less effective in atypical depressive disorders with biological features such as increased sleep and increased appetite. A third systematic review found that tricyclic antidepressants were associated with higher rates of adverse effects than selective serotonin reuptake inhibitors, but the difference was small. One systematic review and two case control studies found no significant difference in risk of suicide between selective serotonin reuptake inhibitors and tricyclic antidepressants. Two RCTs, primarily in people with severe depression, found no significant difference in symptoms at 4 weeks between desipramine or imipramine and reboxetine, but results were sensitive to outcome scales used. One systematic review found no significant difference between milnacipran and imipramine in people with major depressive disorder, although it found an overall higher incidence of adverse events in the imipramine group. One systematic review found no significant difference between low dosage tricyclic antidepressants and standard dosage tricyclic antidepressants in the proportion of responders at 6–8 weeks. One systematic review found that combining antidepressants (primarily tricyclic antidepressants) with benzodiazepines increased response rate within 1 week compared with antidepressants alone, although this difference was not significant at 6 weeks. One systematic review found that imipramine was significantly more effective for treatment of psychotic depression compared with fluvoxamine and mirtazapine.

Benefits

Tricyclic antidepressants versus each other:

We found one systematic review (search date 2000, 136 RCTs, 9150 people) comparing amitriptyline with other tricyclic antidepressants (TCAs). The review found that amitriptyline was significantly more effective compared with other TCAs in an inpatient population (46 RCTs, OR 1.20, 95% CI, 1.02 to 1.42), but not in an outpatient population (31 RCTs, OR 0.98, 95% CI 0.81 to 1.17; 31), on a dichotomous outcome. Similarly, on a continuous outcome the review found that amitriptyline was significantly more effective than TCAs in inpatients (11 RCTs, SMD 0.23, 95% CI 0.03 to 0.44), but not in outpatients (16 RCTs, SMD +0.13, 95% CI –0.14 to +0.40).

Tricyclic antidepressants versus selective serotonin reuptake inhibitors:

See benefits of selective serotonin reuptake inhibitors.

Tricyclic antidepressants versus monoamine oxidase inhibitors:

See benefits of monoamine oxidase inhibitors.

Tricyclic antidepressants versus reboxetine:

See benefits of reboxetine.

Tricyclic antidepressants versus milnacipran:

We found no systematic review but found one RCT which compared milnacipran (50 mg twice daily during a 3 day build up period at the beginning of the study) versus imipramine (50 mg twice daily) for 6 weeks. The RCT did not present results of an intention to treat analysis, and found no significant differences between treatments (100 people aged 18–70 years with major depressive disorder; per protocol analysis of change in Montgomery–Asberg Depression Rating Scale [MADRS] score from baseline: –25.9 with milnacipran v –25.2 with placebo; reported as not significant).

Tricyclic antidepressants versus venlafaxine:

See benefits of venlafaxine versus other prescription antidepressant drugs.

Low dose tricyclic antidepressants versus standard dose tricyclic antidepressants:

We found one systematic review that found no significant difference between low dosage TCAs and standard dosage TCAs in the proportion of responders at 6–8 weeks (search date 2000, 6 RCTs, 551 people; response: RR 1.11, 95% CI 0.76 to 1.61). It is likely that these RCTs were designed to show equivalence between treatments rather than superiority of one over another, so the clinical relevance of this result is unclear.

Tricyclic antidepressants plus benzodiazepines versus tricyclic antidepressants alone:

We found one systematic review (search date 1999, 9 RCTs, 679 people aged 18–73 years with major depression) comparing combination treatment with antidepressant drugs (primarily TCAs) plus benzodiazepines versus antidepressant drugs alone. It found that combination treatment was significantly more likely to produce a response within 1 week compared with antidepressant drugs alone (RR of > 50% reduction on symptom rating scale 1.64, 95% CI 1.19 to 2.27), although this difference was not apparent at 6 weeks.

Psychotic depression:

We found one systematic review (search date 2004, 10 RCTs, 548 people) that compared the effectiveness of drug treatments for people with psychotic depression. Two RCTs included in this review compared imipramine with fluvoxamine (a selective serotonin reuptake inhibitor) and mirtazapine. In the first RCT included in the review imipramine was significantly more effective than fluvoxamine (RR 2.10, 95% CI 1.06 to 4.17, P = 0.03). In the second RCT included in the review imipramine was significantly more effective than mirtazapine (RR 3.00, 95% CI 1.01 to 8.95, P = 0.05). The review found that when data were pooled, TCAs were significantly more effective in treating psychotic depression than non-TCAs (RR 2.36, 95% CI 1.32 to 4.23, P = 0.004).

Harms

Tricyclic antidepressants versus each other:

The review found that there were no statistically significant differences between amitriptyline and other TCAs for withdrawal rates (OR 1.09, 95% CI 0.98 to 1.22; 104 RCTs, 7596 people), either as inpatients (OR 1.16, 95% CI 0.97 to 1.38; 51 RCTs, 3251 people) or as outpatients (OR 1.03, 95% CI 0.90 to 1.19; 53 RCTs, 4345 people).

Tricyclic antidepressants versus selective serotonin reuptake inhibitors:

See harms of selective serotonin reuptake inhibitors.

Tricyclic antidepressants versus monoamine oxidase inhibitors:

See harms of monoamine oxidase inhibitors.

Tricyclic antidepressants versus reboxetine:

See harms of reboxetine.

Tricyclic antidepressants versus milnacipran:

The RCT found a significantly higher incidence of bitter taste, difficulties in concentrating, and diffuse body pain in the imipramine than in the milnacipran group, and a significantly higher incidence of shivering in the milnacipran than in the imipramine group (results presented graphically, no further details reported).

Low dose tricyclic antidepressants versus standard dose tricyclic antidepressants:

The review found that people taking low dose TCAs were 55% (95% CI 24% to 73%) less likely than people taking standard dose TCAs to withdraw because of adverse effects. However, it found no significant difference between low dose and standard dose TCAs in the proportion of people who withdrew for any cause (RR 0.95, 95% CI 0.75 to 1.20).

Tricyclic antidepressants plus benzodiazepines versus tricyclic antidepressants alone:

The review found that TCAs plus benzodiazepines significantly reduced the proportion of people who withdrew from the trial because of adverse effects compared with antidepressants alone (23/342 [7%] with TCAs plus benzodiazepines v 46/337 [14%] with TCAs alone; RR 0.53, 95% CI 0.32 to 0.86).

Tricyclic antidepressants during pregnancy:

One systematic review (search date 1999) assessing the risk of fetal harm of antidepressant drugs (TCAs and selective serotonin reuptake inhibitors) in pregnancy found four small prospective studies published since 1993. It found no evidence of increased risk, although the risk of adverse effects cannot be excluded. See harms of tricyclic antidepressants in review on postnatal depression.

Psychotic depression:

The systematic review gave no information on adverse effects.

Comment

See comment on prescription antidepressant drugs versus placebo.

Substantive changes

Tricyclic antidepressants versus other prescription antidepressants Two systematic reviews added. Categorisation unchanged (Beneficial) but benefits and harms section enhanced.

BMJ Clin Evid. 2007 Jun 15;2007:1003.

Venlafaxine versus other prescription antidepressant drugs

Summary

One systematic review and one RCT found no significant difference between venlafaxine and tricyclic antidepressants in the proportion of people who responded over 1–12 months. Two reviews found that venlafaxine increased the proportion of people who responded compared with selective serotonin reuptake inhibitors as a class, with fluoxetine specifically. Two RCTs found no significant difference between venlafaxine and mirtazapine in proportion of responders at study end point, but found that both treatments improved depressive symptoms from baseline and that mirtazapine can have a faster onset of action.

Benefits

Venlafaxine versus tricyclic antidepressants:

We found one systematic review and one RCT. The systematic review compared venlafaxine versus tricyclic antidepressants (TCAs). It found no significant difference between venlafaxine and TCAs in the proportion of people who responded over 1 month to 1 year (search date 2000, 8 RCTs, 1356 people with mild to moderate depression; response defined as ≥ 50% reduction on continuous rating scale: OR 1.29, 95% CI 0.89 to 1.85; absolute numbers not reported). The subsequent RCT found no significant difference between venlafaxine (mean dose 85.4 mg/day) and amitriptyline (84.1 mg/day) in symptoms of depression (160 outpatients aged 18–65 years, with moderate depression, HAM-D score 20–26; mean reduction in HAM-D from baseline: –10.5 with venlafaxine v –10.4 with amitriptyline; reported as not significant).

Venlafaxine versus selective serotonin reuptake inhibitors:

We found three systematic reviews, which compared venlafaxine versus selective serotonin reuptake inhibitors (SSRIs). The first review found that venlafaxine significantly increased the proportion of people who responded (response defined as ≥ 50% reduction on continuous rating scale) over 1 month to 1 year compared with SSRIs (search date 2000, 20 RCTs, 3844 people with mild to moderate depression: RR 1.26, 95% CI 1.02 to 1.58). The second systematic review (search date 2005, 10 RCTs, 2531 people with major depressive disorder) compared venlafaxine versus three SSRIs (fluoxetine, 7 RCTs, 1939 people; paroxetine, 2 RCTs, 445 people; and sertraline, 1 RCT, 147 people); however, results were only reported for the venlafaxine versus fluoxetine comparison. The review found that venlafaxine was significantly more effective than fluoxetine for the treatment of major depressive disorder (6 RCTs, 1340, relative benefit, 1.12, 95% CI 1.02 to 1.23, no further data reported). Dealing with RCTs in this research field, it is not infrequent to find conflicting evidence. As with comparisons of SSRIs with other SSRIs, RCTs reporting significant differences are frequently funded by a pharmaceutical company, with the company's drug favoured over the comparator. Also, as with the SSRI comparisons, it is very difficult to determine whether the statistically non-significant findings are consistently related to quality ratings, trial duration, sample size, or non-inferiority design. The third review (search date 2004, 9 RCTs, 7 of which were included in the second review, 1891 people with depression) found that venlafaxine was significantly more effective compared with fluoxetine (433/947 with venlafaxine v 361/944 with fluoxetine; RR 1.40, 95% CI 1.15 to 1.70, P = 0.0007).

Venlafaxine versus mirtazapine:

We found no systematic review but found two RCTs. The first RCT found limited evidence that there were fewer responders (50% reduction in HAM-D score) with venlafaxine 75–375 mg daily than with mirtazapine 15–60 mg daily at 8 weeks, although the difference was not significant (157 inpatients aged 18–65 years, HAM-D-17 score ≥ 25; difference in HAM-D: –2.1, 95% CI –5.0 to +0.8; P = 0.154). There were significant improvements in depressive symptoms from baseline for both treatments (change from baseline in HAM-D score: –17.1 with mirtazapine v –14.6 with venlafaxine; both reported as significant). The second RCT (242 people, aged 18–70 years from 23 private practices) compared time of onset of antidepressant action of mirtazapine tablets with venlafaxine extended release formulation in outpatients with major depression over 6 weeks. Both treatments were given in a rapidly escalating dosing regimen (target doses reached by day 6 of treatment: mirtazapine 45 mg, and venlafaxine XR 225 mg). The RCT found that the mean change in baseline HAM-D total score on days 5–15 was greater in the mirtazapine group than in the venlafaxine group (–7.5 with mirtazapine v –5.9 with venlafaxine; P = 0.008); however, no significant differences were found at the end of the 6 week treatment phase. The proportion of responders (HAM-D decrease of ≥ 50% from baseline) was higher in the mirtazapine ODT group on all assessment days, being significant on days 8, 11, and 22 (day 8: 20% with mirtazapine v 6% with venlafaxine; P = 0.002; day 11: 32% with mirtazapine v 16% with venlafaxine; P = 0.004; day 22: 48% with mirtazapine v 34% with venlafaxine; P = 0.027). This paper was supported by the pharmaceutical company marketing mirtazapine. Results are difficult to interpret because the paper did not report the full dataset about primary efficacy outcome.

Harms

Venlafaxine versus tricyclic antidepressants:

The review gave no information on adverse events. The subsequent RCT found a higher incidence of adverse events with amitriptyline compared with venlafaxine (71.4% with amitriptyline v 55.7% with venlafaxine; P = 0.04). Specific adverse drug reactions that occurred more with amitriptyline were digestive tract problems, dry mouth, and other sensory disorders (digestive tract: 43/77 [56%] with amitriptyline v 33/79 [42%] with venlafaxine; P = 0.079; dry mouth: 38/77 [49%] with amitriptyline v 21/79 [27%] with venlafaxine; P = 0.003; other sensory disorders: 3/77 [4%] with amitriptyline v 0/79 [0%] with venlafaxine; P = 0.076).

Venlafaxine versus selective serotonin reuptake inhibitors:

The first review gave no information on adverse effects. The second review found that rates of nausea and vomiting were consistently higher for venlafaxine than for SSRIs. Across venlafaxine trials, the mean incidence of nausea was 31% (95% CI, 27% to 34%). The same review reported for venlafaxine the mean incidence and 95% confidence intervals for specific adverse events that were commonly reported in the other included RCTs (mean incidence: diarrhoea: 5.5, 95% CI 1.0 to 10.1; dizziness: 15.7, 95% CI 7.0 to 24.4; headache: 12.8, 95% CI 8.0 to 17.6; insomnia: 11.2, 95% CI 3.4 to 19.0; nausea: 31.0, 95% CI 27.4 to 34.0). The third review found that withdrawals caused by adverse effects were higher in the venlafaxine group than in the fluoxetine group (106/1014 with venlafaxine v 84/1022 with fluoxetine; OR 0.76, 95% CI 0.57 to 1.03, P = 0.08). In a retrospective study, venlafaxine seemed associated with a statistically significant increase in diastolic blood pressure. In terms of tolerability, another review specifically aimed to systematically compare overall loss to follow up, discontinuation rates because of adverse effects, and discontinuation rates caused by lack of efficacy in published RCTs assessing the relationship between SSRIs and venlafaxine. This review found 10 studies (2314 people) comparing SSRIs with venlafaxine. The overall percentage of loss to follow up was similar between the SSRI group and the venlafaxine group (24% with SSRIs v 25% with venlafaxine; P = 0.826). Accordingly, the pooled relative risks presented no significant difference between SSRIs and venlafaxine for the overall loss to follow up (RR 1.01, 95% CI 0.88 to 1.17). Fewer people on SSRIs than on venlafaxine discontinued because of adverse effects (9% with SSRIs v 11% with venlafaxine; P = 0.121, RR 1.21, 95% CI 0.90 to 1.62). In the SSRIs group, 5.3% of people withdrew because of lack of efficacy, whereas the figure in the venlafaxine group was 4%; the pooled relative risk for discontinuation because of lack of efficacy favoured venlafaxine, but did not reach statistical significance (RR 0.70, 95% CI 0.47 to 1.03; P = 0.053). Results reported in this review are very similar to those reported in a previously mentioned systematic review, even though the second review focused only on the fluoxetine versus venlafaxine comparison, and included three more RCTs not included in the first review.

Venlafaxine versus mirtazapine:

The first RCT found that significantly more people withdrew from the study because of adverse events with venlafaxine than mirtazapine (withdrawals: 12/79 [15.3%] with venlafaxine v 4/78 [5.1%] with mirtazapine; P = 0.037). It found that venlafaxine significantly increased sweating and weight loss compared with mirtazapine (sweating: 35.1% with venlafaxine v 15.8% with mirtazapine; P ≤ 0.05; weight loss: 39.2% with venlafaxine v 21.1% with mirtazapine; P ≤ 0.05). The second RCT found that a total of 86 people discontinued prematurely (39 with mirtazapine v 47 with venlafaxine; no significance assessment performed). Of these, 51 people discontinued because of adverse events (22 with mirtazapine v 29 with venlafaxine; no significance assessment performed), three owing to lack of efficacy (1 with mirtazapine v 2 with venlafaxine), and one (mirtazapine) because of suicide risk. The most frequently reported events in the mirtazapine group were fatigue (29%, no absolute numbers reported), headache (15%, no absolute numbers reported), and dry mouth (15%, no absolute numbers reported); and, in the venlafaxine group, nausea (24%, no absolute numbers reported), fatigue (16%, no absolute numbers reported), headache (15%, no absolute numbers reported), and insomnia (15% no absolute numbers reported). No deaths occurred during the trial.

Comment

See comment on prescription antidepressant drugs versus placebo.

Clinical guide:

A retrospective observational analysis of the General Practice Research Database (GPRD), found that people prescribed venlafaxine were more likely to attempt or complete suicide compared with people prescribed citalopram, fluoxetine, and dosulepin (dothiepin). However, adjustment for several possible confounders substantially reduced the excess risk. In the UK, guidelines currently recommend that venlafaxine treatment should only be initiated by or managed under the supervision of specialist mental health medical practitioners, although the Medicines and Healthcare products Regulatory Agency (MHRA) has recently relaxed this guidance to apply only to those severely depressed or hospitalised patients who require doses of 300 mg daily. Observational evidence indicates that, in suicidal pe who had ever used antidepressants, the current use of any antidepressant was associated with a markedly increased risk of attempted suicide, and with a markedly decreased risk of completed suicide and death. In this analysis, venlafaxine was associated with the highest risk of suicide. Finally, warnings have recently been issued by the US Food and Drug Administration (FDA), by the UK MHRA, and by the drug manufacturer of venlafaxine about the potential risk of cardiotoxicity and toxicity in overdose associated with venlafaxine use. Overall, there is a consistent, albeit unexplained, risk signal with venlafaxine. Despite the evidence for marginally greater efficacy compared with other antidepressants, the current evidence suggests that venlafaxine should not be considered a routine first line treatment for people with major depression.

Substantive changes

Venlafaxine versus selective serotonin reuptake inhibitors Three systematic reviews, one RCT, and one retrospective study added. Benefits and harms sections enhanced. Categorisation unchanged (Beneficial).

BMJ Clin Evid. 2007 Jun 15;2007:1003.

Reboxetine versus other prescription antidepressant drugs

Summary

Two RCTs, primarily in people with severe depression, found no significant difference in symptoms at 4 weeks between reboxetine and desipramine or imipramine, but results were sensitive to outcome scales used. RCTs in people with major depression found similar response rates at 6 weeks between reboxetine, fluoxetine, and sertraline; they also found that reboxetine may slightly improve social functioning.

Benefits

Reboxetine versus tricyclic antidepressants:

We found no systematic review, but found two RCTs. The first RCT compared three interventions: reboxetine 4–8 mg daily (84 people), desipramine 100–200 mg daily (89 people), and placebo (84 people). It found no significant difference between reboxetine and desipramine in the proportion of people who responded (defined as ≥ 50% reduction in HAM-D score) over 4 weeks (258 people aged 18–65 years admitted to hospital with severe depression; response according to HAM-D criteria: 60% with reboxetine v 48% with desipramine; P reported as non-significant, CI not reported). However, it found that reboxetine significantly increased the proportion of people who responded if response was assessed by Clinical Global Impression Scale (CGI) score (response defined as ≥ 50% reduction in CGI: 51% with reboxetine v 33% with desipramine; P < 0.05). This difference in results when assessed by different scales makes it difficult to assess the clinical importance of the difference in outcomes between reboxetine and desipramine. The second RCT compared reboxetine 8–10 mg daily versus imipramine 150–200 mg daily for 6 weeks. It found that reboxetine significantly improved symptoms at 6 weeks measured by HAM-D score (256 people aged 18–65 years with moderate to severe depression, 80% receiving reboxetine and 72% receiving imipramine with severe depression; mean reduction in HAM-D score: 15.8 points with reboxetine v 14.3 points with imipramine; mean difference –1.5, 95% CI –4.0 to –1.0) and increased the proportion of people who responded compared with imipramine (response defined as ≥ 50% reduction in HAM-D: 68.5% with reboxetine v 56.2% with imipramine; difference 12.3%, 95% CI 0.3% to 24.3%). However, it found no significant difference in Montgomery–Asberg Depression Rating Scale score at 6 weeks (mean reduction: 5.9 with reboxetine v 6.0 with imipramine; reported as not significant, CI not reported). This makes the results difficult to interpret.

Reboxetine versus selective serotonin reuptake inhibitors:

We found no systematic review, but found three RCTs. The first RCT compared reboxetine 8–10 mg daily versus fluoxetine 20–40 mg daily. It found that a similar proportion of people responded over 6 weeks with reboxetine and fluoxetine (168 people aged 18–65 years with major depressive disorder without psychotic features; response defined as CGI score of 1 [very much improved] or 2 [much improved]: 78% with reboxetine v 76% with fluoxetine; CI not reported). The second RCT assessed the effects of reboxetine 8–10 mg daily, paroxetine 20–40 mg daily, and placebo on social functioning. It found that reboxetine significantly improved mean Social Adaptation Self Evaluation Scale score at 8 weeks compared with fluoxetine (381 people aged 18–65 years with major depressive disorder without psychotic features; mean score: 35.3 with reboxetine v 31.9 with fluoxetine; P < 0.05). The clinical importance of this difference in scores is unclear. The third RCT (41 people with major depressive disorder) compared reboxetine with sertraline over 11 weeks. The two groups were compared in terms of response (HAM-D ≥ 10) measures. The RCT found that at week 11 the scores were similar and no statistically significant difference was found between the two groups (no further data reported).

Harms

Reboxetine versus tricyclic antidepressants:

The first RCT found that more people taking reboxetine had urinary hesitancy compared with people taking desipramine, although the difference was not significant (11% with reboxetine v 5% with desipramine, no significance reported). However, it found that significantly more people taking desipramine had dry mouth and blurred vision (dry mouth: 21% with desipramine v 13% with reboxetine; blurred vision: 17% with desipramine v 4% with reboxetine; reported as significant, CI not reported). In the second RCT, 81.5% of people taking reboxetine and 81.7% of people taking imipramine had at least one adverse effect. The RCT found that more people taking reboxetine than imipramine had headache, urinary hesitancy, and nausea, but more people taking imipramine had dry mouth, hypotension, insomnia, tachycardia, somnolence, and tremor (CI not reported for any outcome).

Reboxetine versus selective serotonin reuptake inhibitors:

The first RCT found no significant difference between reboxetine and fluoxetine in the proportion of people who had at least one adverse effect (67.1% with reboxetine v 67.4% with fluoxetine; P = 0.307). Adverse events experienced more frequently by people taking reboxetine were dry mouth, constipation, urinary hesitancy, and paraesthesia (dry mouth: 34% with reboxetine v 9 % with fluoxetine; constipation: 21% with reboxetine v 7% with fluoxetine; hypotension: 19% with reboxetine v 8% with fluoxetine; urinary hesitancy: 13% with reboxetine v 1% with fluoxetine; paraesthesia: 6% with reboxetine v 1% with fluoxetine; significance not reported for any outcome). Adverse effects experienced more frequently by people taking fluoxetine were agitation, nervousness, or anxiety (4% with reboxetine v 11% with fluoxetine, significance not reported) and diarrhoea (1% with reboxetine v 7% with fluoxetine; significance not reported). The second RCT gave no information on adverse effects. The third RCT reported that dry mouth, sweating, palpitation, headache, hot flushing, and sedation were more frequent in the reboxetine group.

Comment

Reboxetine versus tricyclic antidepressants:

In the RCTs comparing reboxetine versus a tricyclic antidepressant or placebo in people with severe depression, the high response rates to tricyclic antidepressants, and the low response rates to placebo (20% in 1 RCT and 35% in the other) contrast with those of a previous study using imipramine and amitriptyline. This suggests that response rates to these antidepressants were lower in people with severe depression than in people with mild to moderate depression (proportion of people defined as good responders: 39% with severe depression v 67% with mild to moderate depression).

Substantive changes

Reboxetine versus selective serotonin reuptake inhibitors One RCT added. Categorisation unchanged (Likely to be beneficial) but benefits and harms sections enhanced.

BMJ Clin Evid. 2007 Jun 15;2007:1003.

St John's Wort (Hypericum perforatum)

Summary

One systematic review found that, in people with depressive disorders, St John's Wort ( Hypericum perforatum: ) improved depressive symptoms over 4–12 weeks compared with placebo. The review found no significant difference between St John's Wort and tricyclic antidepressants or selective serotonin reuptake inhibitors. The results of the RCTs should be interpreted with caution, as many did not use standardised preparations of St John's Wort, and doses of antidepressants varied. Questions have been raised regarding the methodological quality of available studies, which have examined heterogeneous patient populations, and inconsistently used standardised symptom rating instruments. St John's Wort is likely to interact with many more drugs than has been previously reported.

Benefits

St John's Wort versus placebo:

We found one systematic review (search date 2004, 26 RCTs, 3320 people with depressive disorders), which compared single preparations of St John's Wort versus placebo in people with depressive disorders. The review restricted some pooling of data to people with major depression (according to Diagnostic and statistical manual of mental disorders [DSM-IV] or International classification of mental and behavioural disorders [ICD-10] criteria), and further split the analysis into smaller and larger RCTs. However, for both the smaller and larger RCTs of the restricted group the review found that St John's Wort was significantly more effective for treating major depression than placebo (smaller RCTs of people with major depression: 157/342 [50%] with St John's Wort v 76/344 [22%] with placebo; RR 2.06, 95% CI 1.65 to 2.59, P < 0.00001; larger RCTs of people with major depression: 346/646 [54%] with St John's Wort v 274/595 [46%] with placebo; RR 1.15. 95% CI 1.02 to 1.29, P = 0.02). RCTs not restricted to major depression were also split into smaller and larger RCTs for data pooling; similarly, the RCT found that, for both smaller and larger RCTs, St John's Wort was significantly more effective than placebo for treating depression (smaller RCTs: 83/167 [50%] with St John's Wort v 13/167 [8%] with placebo; RR 6.13, 95% CI 3.63 to 10.38, P < 0.00001; larger RCTs: 145/242 [60%] with St John's Wort v 87/249 [35%] with placebo; RR 1.71, 95% CI 1.40 to 2.09, P < 0.00001). Response rates in both placebo and intervention groups changed over time, showing that response rates in the placebo groups increased by 1.5% a year (i.e. greater response in more recent studies; P = 0.013) whereas rates decreased in the St John's Wort groups by 1.1% a year (i.e. less response in more recent studies; P = 0.049).

St John's Wort versus tricyclic antidepressants:

We found one systematic review (search date 2005, 1231 people) which compared single preparations of St John's Wort with tricyclic antidepressants (TCAs; amitriptyline [2 RCTs], imipramine [4 RCTs], maprotiline [1 RCT]). The review found no significant differences between St John's Wort and TCAs for the treatment of depression (321/615 [52%] with St John's Wort v 313/616 [51%] with TCAs; RR 1.03, 95% CI 0.93 to 1.14, P = 0.6). There was no evidence of heterogeneity between RCTs.

St John's Wort versus selective serotonin reuptake inhibitors:

We found one systematic review (search date 2005, 6 RCTs, 813 people) which compared single preparations of St John's Wort with selective serotonin reuptake inhibitors (SSRIs; fluoxetine [3 RCTs], sertraline [3 RCTs]). The review found no significant difference between St John's Wort and SSRIs for the treatment of depression (196/410 [48%] with St John's Wort v 200/403 [50%] with SSRIs; RR 0.97, 95% CI 0.85 to 1.12, P = 0.7).

Older adults:

We found no systematic review or RCTs specifically in older adults.

Harms

Two reviews, which included case reports and data from the Adverse Drug Events (ADR) database of the World Health Organization Collaborating Centre for International Drug Monitoring (administered by the Uppsala Monitoring Centre) and from the Medicines and Healthcare products Regulatory Agency (MHRA), found evidence of significant interactions with antidepressant drugs and other drugs which may potentially reduce or enhance plasma levels, or efficacy of various conventional drugs. The clinical importance of drug interaction with St John's Wort depends on several factors associated with co-administered drugs (dose, dosing regimen, administration route, pharmacokinetic and therapeutic range), herb (dose, dosing regimen, administration route), and patients (genetic polymorphism, age, gender, and pathological conditions).

St John's Wort versus placebo:

The systematic review found that slightly fewer people after treatment with St John's Wort compared with placebo withdrew overall (OR 0.82, 95% CI, 0.64 to 1.06), withdrew because of adverse effects (OR 0.61, 95% CI, 0.28 to 1.31), and reported adverse effects (OR 0.79, 95% CI, 0.61 to 1.03), although these differences were not statistically significant.

St John's Wort versus tricyclic antidepressants:

The systematic review found that significantly fewer participants were likely to withdraw with St John's Wort (OR 0.65, 95% CI, 0.46 to 0.92), fewer participants with Hypericum perforatum withdrew because of adverse events compared with TCAs (7 RCTs, 1231 people; OR 0.25, 95% CI 0.14 to 0.45), and reported adverse effects (OR 0.39, 95% CI, 0.31 to 0.50).

St John's Wort versus selective serotonin reuptake inhibitors:

The systematic review found that there was a trend towards a lower probability of withdrawal because of adverse effects (OR 0.60, 95% CI, 0.31 to 1.15) and reporting of adverse effects (OR 0.75, 95% CI, 0.52 to 1.08) for people treated with St John's Wort extracts compared with SSRIs. However, overall withdrawal rates were similar (RR 0.95, 95% CI, 0.65 to1.40).

Comment

Questions have been raised regarding the methodological quality of available studies, which have examined heterogeneous patient populations, and inconsistently used standardised symptom rating instruments. The results of the systematic reviews must be interpreted with caution because the preparations and doses of St John's Wort and types and doses of antidepressant drugs varied widely. RCTs that use standardised preparations of St John's Wort are needed. The interactions of St John's Wort may be partly explained by the induction of hepatic and intestinal systems involved in drug metabolism. As these systems metabolise more than 50% of all therapeutic drugs, St John's Wort is likely to interact with many more drugs than has been previously reported.

Clinical guide:

Even though most available comparisons between St John's Wort and synthetic standard antidepressant drugs suggest similar effects, current best evidence from placebo comparisons showed only minor benefits of St John's Wort in people with major depression, and perhaps no benefit in people with prolonged duration of depression. There is no robust evidence about effectiveness in severe depression.

Substantive changes

St John's Wort One systematic review added. Benefits, harms, and comment sections enhanced. One review added. Harms section enhanced. Categorisation unchanged (Likely to be beneficial).

BMJ Clin Evid. 2007 Jun 15;2007:1003.

Exercise

Summary

One systematic review in younger and older adults found limited evidence from poor quality RCTs that exercise may improve symptoms compared with no treatment, and may be as effective as cognitive therapy. One poor quality RCT in older adults identified by the review found limited evidence that exercise may be as effective as antidepressant drugs in improving symptoms and may reduce relapse over 10 months. One RCT provided more evidence of a modest effect for exercise for the treatment of mildly to moderately depressed adults. A systematic review of yoga found the intervention potentially useful, although the conclusions were limited by the poor methodological quality of the studies.

Benefits

We found one systematic review on all forms of exercise (search date 1999, 14 RCTs, 851 people), one systematic review on yoga, and one subsequent RCT. The systematic review on all forms of exercise found limited evidence that exercise may improve symptoms compared with no treatment, and that exercise may be as effective as cognitive therapy. However, it suggested that these results were inconclusive because of methodological problems in all RCTs included; randomisation was adequately concealed in only three RCTs, intention to treat analysis was undertaken in only two, and assessment of outcome was blinded in only RCT. A later systematic review of yoga (search date 2004, 5 RCTs, 183 people) found the intervention potentially beneficial (no further data reported). However, the included RCTs all used different types of yoga, different comparison groups, and the methodological quality of the studies were poor. The subsequent RCT (80 people with moderate depression, HRDS score of ≥ 12) compared four aerobic treatment groups that varied total energy expenditure over 12 weeks. The RCT found that 41–44% of the group assigned to the highest energy expenditure exercise responded to treatment (≥ 50% reduction in Hamilton Depression Rating Scale score) compared with 23% of non-aerobic exercise controls (P < 0.05).

Older adults:

The systematic review identified one RCT which compared aerobic exercise, sertraline hydrochloride (a selective serotonin reuptake inhibitor), and combination treatment for 16 weeks. It found no significant difference among groups in the proportion of people who recovered (156 people with major depression, aged 50–77 years; those no longer meeting criteria for depression or with a Hamilton Depression Rating Scale [HAM-D] score < 8: 60% with exercise v 69% with sertraline v 66% with combination treatment). A 10 month follow up of this RCT found significantly lower relapse rates with exercise than with antidepressant drugs (30% with exercise v 52% with sertraline v 55% with combination treatment; P = 0.28 for exercise v either treatment). However, about half of people in the medication group engaged in exercise during follow up, making it difficult to draw firm conclusions. The clinical importance of the observed difference at 10 months remains unclear.

Harms

The two reviews and subsequent RCT gave no information about adverse effects.

Comment

There is a need for a well designed RCT of the effects of exercise in people with all grades of depression, assessing clinical outcomes over an adequate time period.

Clinical guide:

There is currently little evidence that exercise is an effective treatment for depression on its own. However, exercise is beneficial for many other reasons, and is often part of activity scheduling in cognitive behavioural therapy. The judicious use of exercise in combination with other effective treatments would seem to make sense in the treatment of depression.

Substantive changes

Exercise One systematic review and subsequent RCT added. Categorisation unchanged (Unknown effectiveness) but benefits and harms sections enhanced.

BMJ Clin Evid. 2007 Jun 15;2007:1003.

Augmenting prescription antidepressant drug treatment with lithium

Summary

RCTs provided insufficient evidence to assess augmentation of prescription antidepressant drug treatment with lithium in younger and older adults with treatment resistant depression.

Benefits

We found one systematic review (search date 2000, 2 RCTs, 50 people aged 18–75 years with major depression who had not responded to a minimum of 4 weeks of imipramine or equivalent) and one subsequent RCT. The systematic review compared lithium augmentation versus placebo augmentation. It found that lithium augmentation significantly increased the proportion of people who responded over 2 weeks compared with placebo; 11/26 [42%] with lithium v 4/24 [17%] with placebo; absolute risk difference 25%, 95% CI 2% to 49%; RR not reported). The subsequent RCT compared lithium augmentation versus placebo augmentation. It found no significant difference between lithium augmentation and placebo in the proportion of people who responded over 6 weeks (35 people with major depression who had failed to respond to at least 1 earlier trial of antidepressant drugs during the current episode of depression or to 6 weeks' treatment with nortriptyline; response defined as ≥ 50% reduction in the HAM-D-17 scores: 2/18 [11%] with lithium v 3/17 [18%] with placebo; reported as not significant, CI not reported).

Harms

The systematic review and subsequent RCT gave no information on adverse effects. For further details about the harms of lithium, see review on bipolar disorder.

Comment

The review and subsequent RCT are likely to have been underpowered to detect a clinically important difference in outcomes.

Clinical guide:

Lithium is sometimes prescribed to augment prescription antidepressant medications. Sometimes a prescription antidepressant medication (e.g. a SSRI) may have led to a clinical improvement and it is felt adding lithium will boost the antidepressant effects. A systematic review found only two RCTs, and the results were not conclusive. Lithium is more commonly prescribed for bipolar disorder as a mood stabiliser.

Substantive changes

No new evidence

BMJ Clin Evid. 2007 Jun 15;2007:1003.

Augmenting prescription antidepressant drug treatment with pindolol

Summary

RCTs provided insufficient evidence to assess augmentation of prescription antidepressant drug treatment with pindolol in younger and older adults with treatment resistant depression.

Benefits

We found one systematic review and one subsequent RCT. The systematic review (search date 2000, 3 RCTs, 106 people aged 18–75 years with major depression who had not responded to a minimum of 4 weeks of imipramine or equivalent) which compared pindolol augmentation versus placebo augmentation. It found no significant difference in the proportion of people who responded over 1–8 weeks between pindolol augmentation and placebo (responders: 10/53 [19%] with pindolol augmentation v 6/53 [11%] with placebo; absolute risk difference +8%, 95% CI –6% to +21%; RR not reported). The meta-analysis is likely to have been underpowered to detect a clinically important difference between interventions. The subsequent RCT (42 people with major depressive disorder who had had an insufficient response to an adequate trial of an SSRI) compared pindolol 7.5 mg versus sham augmentation. The RCT found no significant difference in outcome (results presented graphically).

Harms

The review and subsequent RCT gave no information on adverse effects.

Comment

Clinical guide:

Pindolol is sometimes prescribed to augment prescription antidepressant medications. If a prescription antidepressant medication (e.g. an SSRI) has led to a clinical improvement, it may be felt that adding pindolol will boost the antidepressant effects. However, a systematic review found that three RCTs did not support their use. A rationale for this treatment is that beta-blockers control some of the symptoms of anxiety (e.g. tachycardia) which can accompany depression. However, beta-blockers are not licensed for the treatment of depression.

Substantive changes

Pindolol augmentation One RCT added. Categorisation unchanged (Unknown effectiveness) but benefits and harms section enhanced.

BMJ Clin Evid. 2007 Jun 15;2007:1003.

Continuing prescription antidepressant drug treatment

Summary

One systematic review found that continuing prescription antidepressant drug treatment after recovery reduced the proportion of people who experienced a relapse over 1–3 years compared with placebo. The effect of continuing antidepressant drugs was independent of the underlying risk of relapse, the duration of treatment before randomisation, or the duration of previous antidepressant treatment. Eight subsequent RCTs also found that continuing antidepressant treatment reduced absolute risk of recurrence by up to a half compared with treatment discontinuation. Two RCTs in people aged over 60 years found that continued treatment with dosulepin (dothiepin) or citalopram after recovery reduced the risk of relapse over 1–2 years compared with placebo, but may increase the risk of ischaemic heart disease. One RCT found no benefit of continuing treatment with sertraline compared with placebo for a further 2 years in preventing relapse.

Benefits

We identified one systematic review and eight subsequent RCTs. The review compared continuation treatment with prescription antidepressant drugs versus placebo over 12 months in people who had responded to antidepressant treatment over the previous 1 month to 3 years. It found that, overall, continuing antidepressant drugs in people who had responded to them significantly reduced the proportion of people who relapsed compared with placebo (search date 2000, 31 RCTs, 4410 people with first episode or recurrent depression; numbers relapsing: 465/2527 [18%] with continuing antidepressants v 1031/2505 [41%] with placebo; OR 0.30, 95% CI 0.22 to 0.38). The review found that, in people who had responded to antidepressants after 2 months' treatment, the number needed to treat by continuing antidepressants to prevent one additional relapse over 6 months was 6 (95% CI 5 to 8), to prevent relapse over 12 months 5 (95% CI 4 to 6), and over 18–36 months was 4 (95% CI 3 to 7). In people who had responded to antidepressant drugs and received 4–6 months' treatment, the number needed to treat by continuing antidepressants to prevent one additional relapse over 12 months was 7 (95% CI 5 to 8), and over 18–36 months was 3 (95% CI 3 to 4). The review found that relapse was most likely to occur in the first 12 months after discontinuation of antidepressants (relapse in first 12 months: 19% with continuing antidepressants v 60% with placebo), but the benefits of continuing were apparent for up to 36 months (first relapse over 12–36 months: 10% with continuing antidepressants v 29% with placebo). The eight subsequent RCTs reported results in line with those of the above systematic review, finding that continuation treatment with antidepressants (escitalopram, mirtazapine, venlafaxine, extended release venlafaxine, nefazodone, fluoxetine, paroxetine plus possible augmentation, gepirone) reduced absolute risk of relapse by up to a half compared with treatment discontinuation.

Older adults:

We found three RCTs. The first RCT compared dosulepin (dothiepin) versus placebo. It found that dosulepin significantly reduced the risk of relapse after recovery compared with placebo after 2 years (69 people aged > 60 years, with mild to moderate or severe depression who had recovered sufficiently and consented to enter a 2 year trial of continuation treatment; relapse: RR 0.45, 95% CI 0.22 to 0.96). The second RCT compared citalopram versus placebo for 48 weeks or more. It found that citalopram significantly reduced the proportion of people who relapsed after recovery compared with placebo after 48 weeks (121 people aged > 64 years with major depression who had responded to citalopram 20–40 mg for 8 weeks and who continued to receive the dose they had responded to for a further 16 weeks; proportion who relapsed: 19/60 [32%] with citalopram v 41/61 [67%] with placebo; HR 0.32, 95% CI 0.19 to 0.56). The third RCT compared sertraline versus placebo for a further 2 years. It found no significant difference between sertraline and placebo in the proportion of people who did not relapse after 2 years (113 people aged ≥ 65 years, HAM-D > 17, who had responded to sertraline 50–200 mg/day for 8 weeks; proportion of people not relapsing: 39% with sertraline v 31% with placebo; ARI +8%, 95% CI –12% to +28%).

Harms

Adverse effects seem to be similar to those reported in trials of acute treatment. The review found that significantly more people continuing prescription antidepressant drugs withdrew from the trials compared with people taking placebo (18% with antidepressants v 15% with placebo; OR 1.30, 95% CI 1.07 to 1.59). Six people continuing antidepressant drugs committed suicide (5/767 [0.7%] with maprotiline and 1/185 [0.5%] with sertraline) compared with one person taking placebo (OR 5.96; 95% CI: 0.72 to 49.47).

Older adults:

The first RCT gave no information on adverse effects. However, a case control study found that, after adjustment for confounding factors and the use of other antidepressants, people who had taken dosulepin were significantly more likely to develop ischaemic heart disease than those who had not (OR 1.67, 95% CI 1.17 to 2.36). The second RCT found that, compared with placebo, continuing citalopram significantly increased sweating, tremor, and fatigue (sweating: 4/60 [7%] with citalopram v 3/61 [5%] with placebo; tremor: 3/60 [5%] with citalopram v 0/61 [0%] with placebo; fatigue: 10/60 [17%] with citalopram v 6/61 [10%] with placebo; reported as significant for all outcomes, CI not reported). The third RCT did not report on adverse events.

Comment

None.

Substantive changes

Continuing prescription antidepressant drugs Three RCTs added. Categorisation unchanged (Beneficial) but benefits section enhanced.

Articles from BMJ Clinical Evidence are provided here courtesy of BMJ Publishing Group

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