This Letter reviews clinical evidence for use of antipsychotics for depression. In Canada, two antipsychotic drugs are approved to treat major depressive disorder (MDD) that is not responsive to other treatment. Quetiapine (Seroquel XR) is approved as monotherapy or in combination with conventional antidepressants for symptomatic relief of MDD “when currently available approved antidepressant drugs have failed”.1 Aripiprazole (Abilify) is approved only for adjunctive treatment of adults with “inadequate response to prior antidepressant treatments during the current episode”.2 Olanzapine, risperidone, ziprasidone, and amisulpiride (not available in Canada) have also been evaluated in randomized trials for MDD. This Letter focuses on quetiapine because it is the most studied antipsychotic in this setting.
Significant persistent depression that impairs quality of life and affects work, social and family functioning is called MDD. At its worst, it can lead to suicide. The lifetime prevalence of MDD has been estimated in a systematic review at 6.7 per 100 people.3 Goals of therapy include amelioration of suffering, suicide prevention and restoration of normal functioning. Maintaining employment, positive social interactions and healthy lifestyle are obvious therapeutic targets, but avoiding drug-induced illness and any deleterious effects are equally important. Clinical trials are typically short, with the only measure of effect being symptom-based depression-rating scales.
Drug treatment of depression dates back to 1957, when Swiss psychiatrist Roland Kuhn claimed that imipramine improved severe depression dramatically and rapidly in hospitalized patients.4 The ensuing search for drugs with similar effects led to a number of classes of antidepressant drugs: tricyclics, heterocyclics, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors and others. However, despite widespread use, antidepressants are only marginally better than placebo for all degrees of depression.5-8 Beneficial effects are not dose-dependent.9 Older antipsychotics, e.g. chlorpromazine, haloperidal, loxapine, etc. are rarely prescribed for depression, and then only for psychotic symptoms. The newer antipsychotics are also dopamine antagonists and not devoid of their predecessors’ adverse effects.10
The marketing label “atypical (second generation) antipsychotic” camouflages properties shared with older antipsychotics. With the exception of clozapine, all antipsychotics block dopamine (D2) receptors, cause extrapyramidal symptoms and signs, tardive dyskinesia and elevate plasma prolactin. The parent drugs or their active metabolites also antagonize serotonin, histamine and alpha-receptors. Quetiapine’s active metabolite, norquetiapine, blocks muscarinic cholinergic receptors, causing dry mouth and other anticholinergic effects.1
Drugs of this “class” can induce postural hypotension by blocking alpha receptors. They also cause weight gain, diabetes and hypercholesterolemia. Risperidone, quetiapine and aripiprazole increase mortality when used for behaviour control in dementia.1,2,11
Most use of these antipsychotics worldwide is not for schizophrenia, and much is for “off-label” or unapproved conditions.12 All antipsychotics can impair alertness, concentration and thinking, often in a dose-dependent manner.
Cochrane Systematic Review
The 2012 Cochrane review12 of “second generation” antipsychotics for MDD and dysthymia in outpatients identified 28 studies using 5 drugs (amisulpride, aripiprazole, olanzapine, quetiapineand risperidone). The trials were short; 22 were 12 weeks or less in duration. Outcomes assessed were typically “response” or “remission” derived from scores on the Hamilton Depression Rating Scale (HAM-D) or the Montgomery Asberg Depression Rating Scale (MADRS). The authors concluded there is “limited” or contradictory evidence either for solo antipsychotic therapy or augmentation therapy and that generally, treatment with second-generation antipsychotic drugs was associated with worse tolerability, mainly due to sedation and weight gain. This review has not yet been updated to include all trials for which results are now available.
Quetiapine for MDD
We identified 10 double blind randomised control trials (RCTs) of quetiapine (25-600 mg/d) for MDD13-22 and 1 RCT for MDD with “comorbid fibromyalgia”23. In 9 RCTs, quetiapine monotherapy was compared only with placebo, whereas 2 trials also compared it to duloxetine and escitalopram.16,22 In 4 RCTs, quetiapine (or placebo) was added to standard antidepressants. Most trials were of 6-8 weeks duration, and only one was longer than 9 weeks. Astra Zeneca sponsored all trials, and designed, ran and analysed the 8 largest trials. One RCT involved 237 sites, most sites recruiting very few patients.18
All trials experienced large dropout rates due to adverse effects, higher for quetiapine than placebo. The high incidence of adverse effects made loss of blinding very likely.14 Selection bias due to early loss of participants, high risk of bias due to loss of blinding, plus other biases made meta-analysis inappropriate, as it would only compound the bias. Quetiapine typically reduced depression scores (vs. placebo) by about 2-3/60 points (MADRS) or 4-5/50 points (HAM-D). “Response” or “remission” rates, defined as arbitrary reductions in rating scores, favoured quetiapine by about 10% absolute improvement. These small effects are not clinically significant8 and could easily occur due to biases present in the trials. Furthermore the improvement in the rating scores could be explained by the sedating effect leading to improved sleep. Quetiapine was not better than duloxetine16 or escitalopram22, and adding quetiapine to fluoxetine in one RCT did not improve any outcomes.14 The lack of long-term trials has resulted in Astra Zeneca advising physicians in the Product Monograph to use quetiapine for the shortest time that is clinically indicated: “When lengthier treatment is indicated, the physician must periodically re-evaluate the longterm usefulness of the drug for the individual patient keeping in mind the long-term risks.”1
Harms caused by quetiapine include somnolence or sedation in up to 69% of patients, and anticholinergic effects in up to 57%. Adverse effects include weight gain, diabetes, extrapyramidal symptoms, dizziness and fatigue. There is no evidence that quetiapine reduces suicidality in MDD and effects on cognition were not reported. A single trial took depressed patients who tolerated and were stabilized on quetiapine and randomized them to continuing quetiapine or placebo. This trial demonstrated that in the first 14 days, treatment discontinuation symptoms were increased in the placebo group as compared to quetiapine. The symptoms included headache, insomnia, sweating, chills, nausea and diarrhea.18 Long-term harms are unstudied, however quetiapine carries significant longterm risks associated with weight gain, diabetes and anticholinergic effects.24
Trials of aripiprazole and other antipsychotics studied fewer patients, but showed similar results and are limited by the same methodological biases.12
- Quetiapine has not been shown to improve overall function as monotherapy or when added to an antidepressant for unresponsive major depressive disorder.
- There is insufficient scientific evidence that quetiapine reduces any depression-rating scores. Quetiapine causes sedation, which improves sleep.
- Biased trial methodology exaggerates any apparent benefits, and minimizes disadvantages such as weight gain or other long-term harms.
- Adverse effects include frequent sedation, anticholinergic effects and weight gain. Long-term harms are unknown, but likely include elevated cardiovascular risk related to weight gain and metabolic changes.
- Evidence for other antipsychotics for depression is not better.
- Seroquel XR (quetiapine) Canadian product monograph 2015. http://webprod5.hc-sc.gc.ca/dpd-bdpp/info.do?code=78550 (Accessed August 2015)
- Abilify (aripiprazole) Canadian product monograph 2015. http://webprod5.hc-sc.gc.ca/dpd-bdpp/info.do?code=80784 (Accessed August 2015)
- Waraich P, Goldner E, Somers JM, Hsu L. Prevalence and incidence studies of mood disorders: A systematic review of the literature. Can J Psychiatry 2004; 49(2): 124-38.
- Brown WA, Rosdolski M. The clinical discovery of imipramine. Am J Psychiatry 2015; 172(5):426-9.
- Moncrieff J, Wessely S, Hardy R. Active placebos versus antidepressants for depression. Cochrane Database of Systematic Reviews 2004, Issue 1. Art. No.: CD003012.
- Khan A, Faucett J, Lichtenberg P, Kirsch I, Brown WA. A systematic review of comparative efficacy of treatments and controls for Depression. Holscher C, ed. PLoS ONE 2012; 7(7):e41778.
- Turner EH, Matthews AM, Linardatos E, et al. Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med 2008; 358(3): 252-60.
- Moncrief J, Kirsch I. Empirically derived criteria cast doubt on the clinical significance of antidepressant-placebo differences. Contemporary Clinical Trials 2015; 43:60-2.
- Furukawa TA, McGuire H, Barbui C. Low dosage tricyclic antidepressants for depression. Cochrane Database of Systematic Reviews 2003, Issue 3. Art. No.: CD003197.
- Owens DC. How CATIE brought us back to Kansas: A critical re-evaluation of the concept of atypical antipsychotics and their place in the treatment of schizophrenia. Advances in Psychiatric Treatment 2008; 14(1):17-28.
- Risperdal (risperidone) Canadian product monograph 2014. http://webprod5.hc-sc.gc.ca/dpd-bdpp/info.do?code=13904 (Accessed August 2015)
- Komossa K, Depping AM, Gaudchau A et al. Second-generation antipsychotics for major depressive disorder and dysthymia. Cochrane Database of Systematic Reviews 2010, Issue 12. Art. No.: CD008121.
- McIntyre A, Gendron A, McIntyre A. Quetiapine adjunct to selective serotonin reuptake inhibitors or venlafaxine in patients with major depression, comorbid anxiety, and residual depressive symptoms: a randomized, placebo-controlled pilot study. Depression and Anxiety 2007; 24(7):487-94.
- Garakani A, Martinez JM et al. A randomized, double blind, and placebo-controlled trial of quetiapine augmentation of fluoxetine in major depressive disorder. Int Clin Psychopharmacol 2008; 23: 269-275.
- Bauer M, Pretorius HW et al. Extended-Release Quetiapine as Adjunct to an Antidepressant in Patients With Major Depressive Disorder: Results of a Randomized, Placebo-Controlled, Double-Blind Study. J Clin Psychiatry 2009; 70: 540-549.
- Cutler AJ, Montgomery SA et al. Extended Release Quetiapine Fumarate Monotherapy in Major Depressive Disorder: A Placebo- and Duloxetine-Controlled Study. J Clin Psychiatry 2009; 70: 526-539.
- Weisler R, Joyce M et al. Extended release quetiapine fumarate monotherapy for major depressive disorder: results of a double-blind, randomized, placebo-controlled study. CNS Spectrums 2009; 14: 299-313.
- Liebowitz M, Lam RW, Lepola U et al. Efficacy and tolerability of extended release quetiapine fumarate monotherapy as maintenance treatment of major depressive disorder: a randomized, placebo-controlled trial. Depress. Anxiety 2010; 27: 964–976.
- El-Khalili N, Joyce M et al. Extended-release quetiapine fumarate (Quetiapine XR) as adjunctive therapy in major depressive disorder (MDD) in patients with an inadequate response to ongoing antidepressant treatment: a multi-centre, randomized, double-blind, placebo-controlled study. Int J Neuropsychopharmacol 2010; 13: 917-932.
- Bortnick B, El-Khalili N et al. Efficacy and tolerability of extended release quetiapine fumarate (quetiapine XR) monotherapy in major depressive disorder: A placebo-controlled, randomized study. J Affective Disorders 2011: 128: 83-94.
- Katila H, Mezhebovsky I et al. Randomized, Double-Blind Study of the Efficacy and Tolerability of Extended Release Quetiapine Fumarate (Quetiapine XR) Monotherapy in Elderly Patients with Major Depressive Disorder. Am J Geriatr Psychiatry 2013; 21: 769-784.
- Wang G, McIntyre A et al. A randomized, double-blind study of the efficacy and tolerability of extended-release quetiapine fumarate (quetiapine XR) monotherapy in patients with major depressive disorder. Neuropsychiatric Disease and Treatment 2014; 10: 201-216.
- McIntyre A, Paisley D et al. Quetiapine Fumarate Extended-Release for the Treatment of Major Depression with Comorbid Fibromyalgia Syndrome: A Double-Blind, Randomized, Placebo-Controlled Study. Arthritis & Rheumatology 2014; 66: 451-461.
- Gray SL, Anderson ML, Dublin S, et al. Cumulative Use of Strong Anticholinergics and Incident Dementia: A Prospective Cohort Study. JAMA Intern Med. 2015;175(3):401-407.