We included randomized, controlled double-blind trials, published in any language, that compared antidepressants with placebo or alternative drug treatments. Antidepressants included all tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), noradrenergic reuptake inhibitors, reversible monoamine oxidase inhibitors (MAOIs), bupropion, St. John’s wort, and tryptophan but not mood stabilizers, anticonvulsants, lamotrigine, sulpiride, benzodiazepines, or ECT. Alternative comparator treatments included mood stabilizers, anticonvulsants, and other antidepressants. The inclusion criteria for the review were trials with patients with a current depressive or mixed depressive/manic episode with or without psychotic symptoms who had had at least one previous episode of mania or hypomania, including antidepressant-induced mania or hypomania. Trials that recruited nonbipolar patients as well as bipolar patients were included if they randomly assigned the bipolar patients separately or if the majority of the patients were bipolar. The primary outcome measures for the review were clinical response and remission rates (derived from observer-rated symptom reductions), induction of mania or hypomania, and the overall dropout rate as a proxy measure of the acceptability of treatment.
We searched the Cochrane Collaboration Depression, Anxiety, and Neurosis Controlled Trials Register (December 2002), incorporating results of group searches of MEDLINE (1966 to the present), EMBASE (1980 to the present), CINAHL (1982 to the present), PsycLIT (1974 to the present), PSYNDEX (1977 to the present), and LILACS (1982–1999). These were searched by using the following terms for diagnosis: bipolar III disorder, unipolar mania, rapid-cycling disorder, affective disorders, affective psychosis, bipolar, bipolar disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, depression, depressive psychosis, excited psychosis, hypomania, mania, manic depressive, manic disorder, manic episode, melancholia, mixed depression, mood disorders, bipolar affective disorder, bipolar not otherwise specified, dysphoric mania, manic episode, manic symptoms, schizoaffective disorder, psychoses, psychotic disorders, puerperal psychosis, and reactive depressive psychosis. The terms searched for intervention and antidepressive agents were monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, and tricyclic drugs. The following drug names were also searched: acetylcarnitine, alaproclate, amesergide, amiflamine, amineptine, amitriptyline, amoxapine, befloxatone, benactyzine, brofaromine, bupropion, butriptyline, caroxazone, chlorpoxiten, cilosamine, cimoxatone, citalopram, clomipramine, clorgyline, clorimipramine, clovoxamine, deanol, demexiptiline, deprenyl, desipramine, dibenzepin, diclofensine, dothiepin, doxepin, duloxetine, etoperidone, femoxetine, fluotracen, fluoxetine, fluparoxan, fluvoxamine, idazoxan, imipramine, iprindole, iproniazid, isocarboxazid, litoxetine, lofepramine, maprotiline, medifoxamine, melitracen, metapramine, mianserin, milnacipran, minaprine, mirtazapine, moclobemide, nefazodone, nialamide, nomifensine, nortriptyline, noxiptiline, opipramol, oxaflozane, oxaprotiline, pargyline, paroxetine, phenelzine, piribedil, pirlindole, pivagabine, prosulpride, protriptyline, quinupramine, reboxetine, rolipram, sertraline, setiptiline, teniloxine, tetrindole, thiazesim, thozalinone, tianeptine, toloxatone, tomoxetine, tranylcypromine, trazodone, trimipramine, venlafaxine, viloxazine, viqualine, and zimeldine.
The Cochrane Library was searched by using the same terms as the Cochrane Collaboration Depression, Anxiety, and Neurosis Controlled Trials Register excluding references that came from that database. The reference lists of selected studies were inspected for more published reports and citations of unpublished research. In addition, other relevant papers and major textbooks that cover affective disorder were checked.
Two of us (H.J.G., J.M.R.) independently checked studies generated by the search strategy to ensure that they met the inclusion criteria. Any disagreement was resolved by consensus discussion with another coauthor (J.R.G.). One reviewer (H.J.G.) assessed the methodological quality of the included studies according to the reporting of the randomization procedure, especially allocation concealment (15), blinding, and the reporting of withdrawals. Information about participant characteristics, intervention details, and outcome measures was extracted independently by two reviewers.
Data were entered twice into Revman 4.2, a program developed by the Cochrane Collaboration for systematic reviews. For binary efficacy outcomes, a pooled relative risk (with 95% confidence intervals [CIs]) was calculated by using both fixed- and random-effects models to investigate the sensitivity of results to the choice of statistical method. Heterogeneity between studies was assessed by using the Q statistic (16). When significant heterogeneity was identified, sources were investigated by visual inspection of the forest plots for outlying trials. Two sensitivity analyses were conducted, one excluding two trials that included less than 100% bipolar patients and another including a trial with bipolar patients who were not randomized separately from unipolar patients. Treatment effects are also presented as the number needed to treat, which is the reciprocal of the absolute difference between the response rates of the compared treatments. The number needed to treat can assist clinical interpretation of the results of trials and expresses the number of patients that must be treated with the drug of interest to achieve one positive outcome more than would be achieved with a comparator or placebo (17).