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From the Editor

Combination therapy is here to stay

The negative connotation of polypharmacy will fade as combination therapies become the new standard of care

Vol. 9, No. 5 / May 2010

Although psychiatrists commonly combine psychotropic medications, researchers malign the practice as “not evidence-based.” Research is finally catching up with clinical practice, however, and evidence is rapidly accumulating that for many patients with severe psychiatric disorders, 2 drugs are better than 1.

This should not be surprising because “real world” patients with schizophrenia, bipolar disorder, major depression, anxiety disorders, or obsessive-compulsive disorder (OCD) often do not achieve remission and are hobbled—even disabled—by their illness without combination therapy. The same principle holds true for general medical illnesses such as hypertension, cancer, or diabetes, where combination therapy is the norm rather than the exception.

Recent studies have confirmed better efficacy with combination therapy compared with monotherapy for several psychiatric illnesses:

Unipolar depression. Blier et al1 demonstrated a remarkable superiority of 3 different combinations of 2 antidepressants compared with fluoxetine monotherapy. The remission rate with combination therapy (46% to 58%) was double that of fluoxetine alone (25%). When 1 of the 2 antidepressants was blindly discontinued in high responders, 40% relapsed. Tolerability to the combination was the same as to monotherapy. Recent FDA approval of 2 atypical antipsychotics—aripiprazole2 and quetiapine3—as adjuncts to antidepressants to increase the remission rates further supports the case for combination therapy.

Bipolar disorder. Psychiatrists know that combining a mood stabilizer with an antipsychotic exerts more efficacy that either drug alone.4 But what about combining 2 mood stabilizers? A recent study5 confirmed the superiority of combining lithium plus valproate compared with either 1 alone. Score another victory for polypharmacy in bipolar disorder, where FDA studies of combination therapy are more common than in any other psychiatric disorder.

Schizophrenia. It is highly unrealistic to expect 1 drug (such as a dopamine antagonist) to show efficacy for schizophrenia’s disparate symptoms, including positive symptoms, negative symptoms, cognitive impairment, mood dysregulation, and substance use. Yet antipsychotic monotherapy remains the standard of care in schizophrenia, and there are no FDA combination trials of antipsychotics. However, in the United States, more than one-third of persons with chronic schizophrenia receive ≥2 antipsychotics because their psychiatrist found that combinations exerted more efficacy compared with just 1 antipsychotic agent. A combination of 2 atypical antipsychotics may be superior to monotherapy, but controlled studies have not been conducted.

In addition, patients receiving clozapine for refractory schizophrenia experienced significant improvement with the addition of lamotrigine.6 Another anticonvulsant, valproate, also was shown to accelerate response to an antipsychotic.7 Clinical trials are being conducted for new agents that enhance memory8 and negative symptoms.9 If the results are positive, the future of schizophrenia pharmacotherapy will shift decisively to polytherapy of 3 or even 4 drugs targeting positive, negative, cognitive, and mood symptoms.10

Anxiety. Recent studies confirm the benefits of combining small doses of atypical antipsychotics to an antidepressant/anxiolytic regimen.11 Most Patients with anxiety receive benzodiazepines as well.

OCD. Most patients with OCD do not achieve a remission with a selective serotonin reuptake inhibitor. Many studies have indicated additional improvement from adding an atypical antipsychotic.12 Other studies have added the glutamate modulating agent memantine with reported benefit.

The writing is now on the psychopharmacology wall: Although many psychiatric patients achieve some response to a single agent, combination therapy often leads to higher remission rates, which is the foremost goal of pharmacotherapy. The negative connotation of polypharmacy will fade as combination therapies become the new standard of care rather than a reviled clinical practice.


1. Blier P, Ward HE, Tremblay P, et al. Combination of antidepressant medications from treatment initiation for major depressive disorder: a double-blind randomized study. Am J Psychiatry. 2010;167(3):281-288.

2. Berman RM, Fava M, Thase ME, et al. Aripiprazole augmentation in major depressive disorder: a double-blind, placebo-controlled study in patients with inadequate response to antidepressants CNS Spectr. 2009;14(4):197-206.

3. El-khalili N, Joyce M, Atkinson S, 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 multicentre, randomized, double-blind, placebo-controlled study in patients with inadequate response to antidepressants. Int J Neuropsychopharmacol. 2010;23:1-16.

4. Sachs GS, Gardner-Schuster EE. Adjunctive treatment of acute mania: a clinical overview. Acta Psychiatr Scand. 2007;116(s434):27-34.

5. Geddes JR, Goodwin GM, Rendell J, et al. Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial Lancet. 2010;375(9712):385-395.

6. Tiihonen J, Wahlbeck K, Kiviniemi V. The efficacy of lamotrigine in clozapine-resistant schizophrenia: a systematic review and meta-analysis. Schizophr Res. 2009;109(1-3):10-14.

7. Casey DE, Daniel DG, Wassef AA, et al. Effect of divalproex combined with olanzapine or risperidone in patients with an acute exacerbation of schizophrenia. Neuropsychopharmacology. 2003;28(1):182-192.

8. Ribeiz SR, Bassitt DR, Arrais JA, et al. Cholinesterase inhibitors as adjunctive therapy in patients with schizophrenia and schizoaffective disorder: a review and meta-analysis of the literature. CNS Drugs. 2010;24(4):303-317.

9. Wolff-Menzler C, Hasan A, Malchow B, et al. Combination therapy in the treatment of schizophrenia. Pharmacopsychiatry. 2010 [ePub ahead of print].

10. Correll CU, Rummel-Kluge C, Corves C, et al. Antipsychotic combinations vs monotherapy in schizophrenia: a meta-analysis of randomized controlled trials. Schizophr Bull. 2009;35(2):443-457.

11. Gao K, Sheehan DV, Calabrese JR. Atypical antipsychotics in primary generalized anxiety disorder or comorbid with mood disorders. Expert Rev Neurother. 2009;9(8):1147-1158.

12. Matsunaga H, Nagata T, Hayashida K, et al. A long-term trial of the effectiveness and safety of atypical antipsychotic agents in augmenting SSRI-refractory obsessive-compulsive disorder. J Clin Psychiatry. 2009;70(6):863-868.

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