B. Somatic Treatments of Acute Depressive Episodes

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Somatic treatments that have been studied in bipolar depression include lithium, anticonvulsants, antidepressants, and ECT. Open studies and case reports comprise most of the literature on the treatment of bipolar depression, with the best-controlled data relating to treatment with lithium, lamotrigine, and paroxetine.

In general, the goals for treatment of acute depression in a patient with bipolar disorder are identical to those for patients with nonbipolar depression. The primary goal is remission of the symptoms of major depression and a return to normal levels of psychosocial functioning. Concerns about precipitation of a manic or hypomanic episode introduce management issues in the treatment of bipolar depression that do not exist for unipolar depression. This section will present efficacy data on lithium, anticonvulsants, antidepressants, ECT, and novel treatments. Information on side effects and implementation and dosing issues for lithium and the anticonvulsants are presented in this guideline in their respective sections under "Somatic Treatments of Acute Manic and Mixed Episodes" (Section V.A). Information on side effects and implementation and dosing issues for the antidepressants is provided in the APA Practice Guideline for the Treatment of Patients With Major Depressive Disorder (2; included in this volume).


1. Lithium

There have been eight placebo-controlled studies of lithium in the treatment of bipolar depression that had five or more subjects. All of these studies employed crossover designs, and all were completed before 1980 (for a review, see Zornberg and Pope [326]). Among a total of 160 patients, the overall rate of response to lithium, regardless of the degree of improvement or relapse with placebo, was 79%. However, the "unequivocal" lithium response rate, defined as a good or moderate response to lithium with a subsequent relapse when given placebo, was much lower (36%). An additional consideration in the use of lithium as an antidepressant is its time to onset (6–8 weeks), which is later than its antimanic effect (326).


2. Anticonvulsants

a) Divalproex and sodium valproate

There have been no published controlled studies of valproate in the treatment of bipolar depression. In an unpublished study, 43 subjects with bipolar I or bipolar II depression were entered into an 8-week, double-blind, placebo-controlled trial of divalproex. Forty-three percent of divalproex-treated patients and 27% of placebo-treated patients achieved recovery, defined as an improvement of '‰¥50% in score on the 16-item Hamilton Depression Rating Scale in the absence of hypomania (Young Mania Rating Scale score <10). This difference was not statistically significant (Gary Sachs and Michelle Collins, personal communication). While these results suggest that divalproex may be useful in the treatment of bipolar depression, a more definitive study is needed.

b) Carbamazepine

In a double-blind, placebo-controlled crossover study (327), four of nine patients with bipolar depression showed significant improvement from baseline in depressive symptoms with carbamazepine treatment.

In an open study of carbamazepine (328), there were significant reductions from baseline in 17-item Hamilton depression scale scores among 27 patients with bipolar depression and nine patients with mixed episodes. Patients with mixed episodes were significantly less likely to have a remission than those with bipolar depression.

c) Lamotrigine

Lamotrigine at doses of 50 mg/day and 200 mg/day was compared with placebo in a 7-week double-blind trial in 195 patients with bipolar I disorder with major depression (329). Both lamotrigine groups reported significantly better response rates on the Montgomery-Åsberg Depression Rating Scale but not on the Hamilton depression scale. The first significant lamotrigine versus placebo difference in Hamilton depression scale scores occurred at week 5 in the patients receiving 200 mg/day, whereas it occurred at week 7 in those given 50 mg/day. Switches into manic or hypomanic episodes occurred at equivalent rates (3%–8%) among the three groups.

In a flexible-dose, placebo-controlled study of lamotrigine in 206 patients with bipolar I or bipolar II major depression (330), both treatment groups improved significantly (response rate to lamotrigine was 50%, response rate to placebo was 49%), but lamotrigine did not distinguish itself from placebo. Lamotrigine was started at 25 mg/day and titrated over 5–6 weeks to the target dose of 400 mg/day. In a subgroup analysis, the patients with bipolar I disorder given lamotrigine did respond significantly better than those given placebo in terms of Montgomery-Åsberg Depression Rating Scale score (mean change of 13.5 versus 10.1, respectively).

In a double-blind, crossover study of patients with refractory, rapid-cycling bipolar I or bipolar II disorder who were treated with lamotrigine, gabapentin, or placebo, 45% of the depressed patients responded to lamotrigine, compared with response rates of 26% for gabapentin and 19% for placebo (284).

Finally, in an open study of patients with refractory bipolar disorder, 48% of 40 depressed patients treated with lamotrigine showed a marked response, and 20% showed a moderate response (331).

The most common side effects of lamotrigine in the treatment of depression are headache, nausea, infection, and xerostomia (39, 329). However, none of these occurred at significantly higher percentage than with placebo (332).

The risk of serious rash, including Stevens-Johnson syndrome and toxic epidermal necrolysis, was found to be higher in patients treated for epilepsy in the first year after the introduction of lamotrigine in Europe (333). In clinical trials for epilepsy, the incidence of serious rash was approximately 0.3% in adults and approximately 1% in children (334, 335). However, with a slow titration schedule, the risk of serious rash was reduced to 0.01% in adults (329), which is comparable to that of other anticonvulsant medications. Rash can occur at any time during treatment but is more likely to occur early in treatment. It may also be more likely if lamotrigine and valproate are administered concomitantly (334, 335). Whenever lamotrigine is prescribed, patients should be apprised of the risk of rash and urged to contact the psychiatrist or primary care physician immediately if a rash occurs. At rash onset, it is difficult to distinguish between a serious and a more benign rash. Particularly worrisome are rashes accompanied by fever or sore throat, those that are diffuse and widespread, and those with prominent facial or mucosal involvement. In such circumstances lamotrigine (and concurrent valproate) should be discontinued.

Lamotrigine should be administered at 25 mg/day for the first 2 weeks, then 50 mg/day for weeks 3 and 4. After that, 50 mg can be added per week as clinically indicated. With concurrent valproate treatment, pharmacokinetic interactions lead to lamotrigine levels that are approximately twice normal. To minimize the risk of potentially serious rash in patients who are receiving valproate, the dose schedule should be cut in half (i.e., 12.5 mg/day or 25 mg every other day for 2 weeks, then 25 mg/day for weeks 3 and 4). Similarly, concurrent carbamazepine treatment leads to an increase in lamotrigine metabolism and requires dosing to be doubled. Further details of lamotrigine dosing and adverse effects can be found in several reviews (262, 334–337).

d) Topiramate

There are no placebo-controlled trials of topiramate in the treatment of bipolar depression, but several trials have suggested its efficacy as an add-on therapy. McIntyre et al. (338) conducted a single-blind, add-on study of topiramate and sustained-release bupropion in depressed patients with bipolar I or bipolar II disorder. Both groups had significant baseline-to-endpoint reduction in 17-item Hamilton depression scale and Clinical Global Impression (CGI) improvement scores, with no difference between the two groups. Thirty-three percent of patients receiving cotreatment with topiramate discontinued treatment because of adverse events compared with 22% of the patients receiving bupropion alone. The most common adverse events were sweating, blurred vision, difficulty sleeping, tremors, and paresthesia.

Hussain (339) conducted an open-label, add-on, 6-month study with topiramate in depressed patients with bipolar I or bipolar II disorder. Of 45 patients, 19 fully responded (Hamilton depression scale score=3–7), and 12 partially responded (Hamilton depression scale score=8–12). Five patients discontinued treatment because of lack of efficacy, and nine discontinued because of adverse events.

Conversely, in an open study of patients with bipolar I or bipolar II disorder, the 11 patients who were initially depressed and received add-on topiramate treatment had no significant improvements in either CGI or Inventory of Depressive Symptomatology scores (316).


3. MAOI antidepressants

a) Tranylcypromine

The efficacy of tranylcypromine was compared with that of imipramine in 56 outpatients with bipolar I or bipolar II depression (340). Compared with imipramine (at doses of at least 150 mg/day), tranylcypromine (at doses of at least 30 mg/day) produced significantly superior outcomes in terms of lower attrition, greater symptomatic improvement, and higher global response without a greater risk of treatment-emergent hypomania or mania.

In a second study (341), tranylcypromine was compared with imipramine in a double-blind crossover fashion for the 16 nonresponsive patients with bipolar I or bipolar II disorder from the previous trial. Tranylcypromine had comparatively better results, including lower attrition, greater symptomatic improvement, higher global response, and no greater risk of precipitating a switch into hypomania or mania.

b) Moclobemide

Moclobemide was compared to imipramine in a 4-week, multicenter, randomized study of 381 patients (342). No significant differences in efficacy were observed between the groups (both had response rates of 58%). The number of patients with adverse events and the total number of adverse events were greater in the imipramine group.


4. SSRIs and other newer antidepressant agents

a) Fluoxetine

Fluoxetine was compared with imipramine and placebo in 89 patients with bipolar depression. Twenty-two of the 89 patients were also taking lithium during the study. Eighty-six percent of the patients receiving fluoxetine over 6 weeks improved compared with 57% receiving imipramine and 38% given placebo. The response rate with fluoxetine was significantly better than that of both imipramine (p<0.05) and placebo (p=0.005). There were significantly fewer fluoxetine patients who discontinued treatment because of adverse events (343).

b) Paroxetine

Paroxetine was studied as an add-on treatment in three double-blind studies of patients with bipolar depression. In one study (344), depressed patients with bipolar I or bipolar II disorder maintained on regimens of lithium or divalproex were randomly assigned either to addition of paroxetine or a combination of lithium and divalproex in a 6-week outpatient trial. In terms of improvement from baseline in 17-item Hamilton depression scale scores, both treatments were equally effective at week 6: the mean scores of 6 and 9 in the subjects given lithium plus divalproex and those treated with adjunctive paroxetine, respectively, represented a decrease of 50%–70% (p<0.001). There were more dropouts among those treated with the combination of lithium and divalproex.

In a placebo-controlled multicenter trial of paroxetine and imipramine in the treatment of patients with bipolar I depression maintained on a regimen of lithium (345), imipramine and paroxetine were found to be superior to placebo in patients whose serum lithium level was 0.8 meq/liter. In those patients with serum lithium levels >0.8 meq/liter, there were no differences among the groups. Of the patients receiving imipramine, treatment-induced switches into manic or hypomanic episodes occurred in 6% of those with lithium levels >0.8 meq/liter and 11% of those with lithium levels 0.8 meq/liter. Switches occurred in none of the paroxetine-treated patients and in 2% of the placebo group (all of whom had lithium levels 0.8 meq/liter).

Paroxetine and venlafaxine were studied in the treatment of patients with bipolar depression on a maintenance medication regimen (346). Forty-three percent of the paroxetine group and 48% of the venlafaxine group were rated as having responded (difference not significant). Whereas switches to episodes of mania or hypomania occurred in 3% of those treated with paroxetine, the rate of switching in the venlafaxine group was 13%.

c) Citalopram

In a 24-week, open-label trial, the use of citalopram as an add-on treatment was studied in 45 patients with bipolar depression (30 [67%] with bipolar I disorder) who were receiving lithium, valproate, or carbamazepine (347). Of the 33 patients who completed the 8-week acute phase, 64% responded, and most of these patients continued to improve through the 16-week continuation phase.

d) Bupropion

There have been two controlled studies of bupropion in the treatment of bipolar depression. In a double-blind, 8-week study (348), patients who had been maintained on regimens of lithium, valproate, or carbamazepine were randomly assigned to bupropion or desipramine treatment. The response rate was 55% for bupropion and 50% for desipramine, a nonsignificant difference. In the first 8 weeks, 30% of the patients receiving desipramine switched into a manic episode, whereas 11% of those receiving bupropion did. Over the entire study, with follow-up to 1 year, the observed rate of switching into manic or hypomanic episodes in patients receiving desipramine was 50%, whereas the rate was 11% with bupropion.

In a 6-week, double-blind study of bupropion versus idazoxan (a selective 2 antagonist) in 16 patients with bipolar I disorder—some of whom were also on a maintenance regimen of lithium—no significant differences were seen between the groups (349).

e) Venlafaxine

In addition to the aforementioned double-blind study that compared venlafaxine with paroxetine (346), another study reported on 15 depressed women with bipolar II disorder who were treated with venlafaxine (350). Sixty-three percent of the patients experienced a 50% reduction from baseline in scores on the 21-item Hamilton depression scale. Two patients (13%) discontinued treatment because of adverse events.


5. Tricyclic antidepressants

Imipramine and desipramine have been used as active control treatments in studies of tranylcypromine, fluoxetine, paroxetine, and bupropion. In general, the tricyclic antidepressants had response rates that were equivalent to or poorer than that of the active comparator (yet superior to placebo). In addition, treatment with tricyclic antidepressants was associated with higher rates of switching into manic or hypomanic episodes.


6. Antipsychotics

In an 8-week, double-blind study of olanzapine monotherapy, olanzapine and fluoxetine combination therapy, and placebo in the treatment of 833 patients with acute bipolar I depression, olanzapine monotherapy and combination therapy were both significantly better than placebo at endpoint (M. Tohen, personal communication, 2001). Furthermore, both of these treatment regimens showed significant separation from placebo at week 1.


7. ECT

Several controlled studies of ECT in patients with bipolar depression were conducted several decades ago (326). All found ECT to be as or more effective than MAOIs, tricyclic antidepressants, or placebo. ECT is a viable option for patients with severe bipolar depression, especially if psychotic features are present (110). For information on side effects and implementation of ECT, see the APA Task Force Report on ECT (110).


8. Novel treatments

Several studies have suggested that sleep deprivation has an antidepressant effect in patients with bipolar depression, although its effect is usually short-lived (351). It has been studied in conjunction with pindolol in a placebo-controlled protocol (352). Forty patients with bipolar depression were randomly assigned to receive either pindolol or placebo in combination with total sleep deprivation. Fourteen of 20 patients who underwent total sleep deprivation while receiving pindolol were rated as having responded (Hamilton depression scale score <8), whereas only one patient receiving placebo and pindolol responded. No switches into manic episodes were observed. Another study examined the value of phototherapy or lithium in conjunction with total sleep deprivation among 115 patients with bipolar depression (353). The authors reported that each adjunctive treatment improved total sleep-deprivation response rates, but the combination of all three added nothing.

Thyroid hormones, particularly thyroxine (T4), have been reported to be useful in the treatment of bipolar disorder, particularly rapid cycling (205). In patients with nonbipolar depression, triiodothyronine (T3) augmentation is associated with an antidepressant effect. The use of thyroid hormones in patients with bipolar depression remains to be studied.

The use of other agents, such as risperidone, olanzapine, ziprasidone, omega-3 fatty acids (354), pramipexole (355), or interventions such as phototherapy (353), vagus nerve stimulation (356), or repetitive transcranial magnetic stimulation (357) requires further study.


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