Although anti-depressants have gotten a bad reputation in the treatment of Bipolar Disorder, two large new prospective demonstrate that anti-depressants do help Bipolar depression, that they do not appear to increase manic episodes as much as feared, and that if they are discontinued, depressive relapses are much more common.  Also, depression is actually the much more common and a more serious risk for bipolar patients than is hypomania or even mania.  

Much of the current crusade to diagnose everyone one as bipolar and to attack the use of anti-depressants for bipolar depression is funded by drug companies making so-called mood stabilizers.  The favored university-affiliated psychiatrists lead the crusade with the help of the American Psychiatric Association.

Of course, patients with clear bipolar illness should simultaneously receive a medicine to block manic episodes.  Lithium is the ideal.  Geodon is my preferred back-up because of its relatively lower cost when given as a once-a-day dosing and its absence of weight gain.  However, anti-depressants are considerably underused in treating bipolar depression.  Indeed, many patients are allowed to wallow in depression for extended periods of time.

Anti-Depressants Don't Increase Risk of Bipolar Mania: Previous research showed that bipolar-1 patients on medicine to block mania were at no increased risk of developing mania if given an anti-depressant as well.  These patients actually did better, since depression is the major difficulty in bipolar illness, occurring four times more often than mania. New research, presented by Christine Truman at the New Clinical Drug Evaluation Unit sponsored by NIMH found that the rate of switches into mania during 511 episodes of major depression in 125 patients with bipolar II disorders occurred no more often in the eight weeks after treatment with anti-depressants compared to the eight weeks before the onset of the major depressive episode.  Also, there was no difference in the 186 major depressive episodes treated with anti-depressants vs. the 325 episodes treated without anti-depressants. Clin Psych News 11-0/5 p. 28. 

Manic Switches on Anti-Depressants Exaggerated? Very Rare with Duloxetine: Bipolar disorder is often undetected, with the most common misdiagnosis being unipolar depression. Studies have suggested that treatment of bipolar and unipolar depression with heterocyclic TCAs may increase the risk of switch rate to mania. In a retrospective analysis of data from eight PC DB studies of duloxetine in patients with non-bipolar major depression, one case of mania occurred in the placebo group (0.1%), and two cases of hypomania were observed in the duloxetine-treated group (0.2%). Among hypomanic-like symptoms, only insomnia was significantly higher in the duloxetine group than in the placebo group (p<0.05). Is treatment-associated hypomania rare with duloxetine: secondary analysis of controlled trials in non-bipolar depression. Dunner DL, et al. University of Washington, Seattle. . J Affect Disord. 2005 Jul;87(1):115-9. Ed: Duloxetine is still covered by patent, so its manufacturer is out there defending it.  The manufacturers of mood stabilizers and atypical anti-psychotics and their favorite academic psychiatrists are leading the charge attacking anti-depressant for Bipolar depression. 

     While the duloxetine studies were short in duration, if an anti-depressant actually causes a manic switch, it is more likely early in treatment.  Since few of the manias occurring with other anti-depressants were ever compared to the placebo rates in double-blind studies, it is actually impossible to be certain how many of the manic switches were caused by the anti-depressants.  It is noteworthy that many patients on lamotrigine became manic in research studies. Thanks to having a placebo group, the industry can say that the lamotrigine didn't cause the manias.  Very few studies with standard anti-depressants in the treatment of bipolar depression have ever been funded by the industry, because at the time there were no other options being promoted for bipolar depression.  The drug companies knew that their popular anti-depressants would be used. After several decades of anti-depressants being used to treat millions of bipolar depressed patients, the drug company's academic psychiatrists are being disingenious and highly irresponsible in saying that anti-depressant treatment of bipolar depression is harm, their claims are not evidence based.  However, there are now two excellent studies showing keeping bipolar patients on anti-depressants is the right thing to do and actually reduces the risk of a manic switch.

Texas Department of State Health Services Strongly Influenced by Pharmaceutical Industry: The pharmaceutical industry has been pouring money into Texas psychiatric departments knowing that this will influence their psychiatrists and thereby influence the State Health Services Treatment Guidelines (J Clin Psychiatry Aug '05).  Texas recommends lamotrigine as the sole first line treatment for Bipolar I depression despite the fact that it has never once been compared to the much less expensive standard anti-depressants and despite the fact that most BD1 patients are already on an antimanic agent.  Also, the only large study of BD1 depression found lamotrigine no better than placebo for preventing relapse. Texas also strongly favors the two most expensive atypical antipsychotics, olanzapine (Zyprexa) and quetiapine (Seroquel), despite the fact that both are fattening and cause more diabetes than the much less expensive once-a-day ziprasidone (Geodon).  They also promote divalproex (Depakote) as a first line treatment for manic episodes despite its very high suicide rate compared to lithium.  Texas makes no mention of folate or omega-3 fatty acids despite their benign nature and, at least in the case of folate, proven efficacy.  Surprisingly, Texas still promotes the expensive topiramate (Topamax) for mania despite multiple double-blind studies proving that it is worthless.  For unknown reasons, Texas doesn't like aripiprazole despite its lack of weight gain vs. Depakote and olanzapine which cause huge amounts of weight gain.  Since more and more psychiatrists are calling everyone that depressed bipolar, lamotrigine will be used far in excess of what its skimpy research would suggest sensible. 

Canadian Guidelines Also Suspicious: Canadian CANMAT guidelines put anti-depressants paired with an anti-manic agent as a first line treatment (Bipolar Disord. 2005;7 Suppl 3:5-69.). However, the rate of mania induction by anti-depressants like bupropion are very small and I think that there is a serious risk in over prescribing anti-manic therapies in the overuse of the Bipolar diagnosis. However, the CANMAT also promotes lamotrigine as a first line treatment with very little research support for the designation. CANMAT appears to have been heavily influence by the University of British Columbia which received industry funding for a huge lamotrigine study, which interestingly found lamotrigine worthless for preventing bipolar depression! A UBC psychiatrist has been promoting lamotrigine as part of the "ideal" treatment despite his own research showing that it did no better than placebo for preventing relapse in Bipolar depression.

APA Guidelines Against Anti-Depressants Criticized by Europeans: Drug industry researchers, such as Ghaemi of Harvard (Bipolar Disord. 2003 Dec;5(6):421-33), have helped lead the crusade against using anti-depressants for bipolar patients, despite a long history of success, including several studies showing value at preventing depression relapse in bipolars, depressed, patients.  The American Psychiatric Association 2002 guidelines were heavily influenced by academic researchers with strong ties to pharmaceutical companies and well documented tendencies to exaggerate the benefits of their patrons drugs.  

Prospective Study Says Leave Bipolar Patients on Their Anti-Depressants: There is a strong movement against using anti-depressants in Bipolar patients due to fear of anti-depressants causing rapid cycling and manic episodes.  However, a large prospective 1-year study of 127 Bipolars randomly assigned to 10 weeks of bupropion, venlafaxine, or an SSRI and either reassigned if their depression didn't respond of randomized to discontinue the anti-depressant to stay on it for one year found that the anti-depressants did not increase manic episodes but that continuing them cut depressive relapses in half from 70% to 35%. A companion 258 patient study with daily assessment also found that patients spent three times as long during the year suffering from depression as from mania or hypomania. At least half of the hypomania/mania possibly induced by anti-depressants led to no or minimal dysfunction. A re-evaluation of the role of antidepressants in the treatment of bipolar depression: data from the Stanley Foundation Bipolar Network. Post RM, Leverich GS, et al. Bipolar Disord. 2003 Dec;5(6):396-406

Adding Anti-Depressant Better Tolerated: 27 outpatient bipolars with depression while on divalproex or lithium. DB. 6 weeks. Those given paroxetine all completed trial but 6 of 16 given a second mood-stabilizer dropped out (2 s-e, 2 noncompliance, 1 medical, 1 mixed state). Depression improved equally. Young, Hamilton, Ont, Am J Psychiatry 00;157:124

Bupropion Preferred for Bipolar Depression, But Infrequently Used: Bupropion has lower manigenic properties but only makes up 8% of anti-depression treated in Bipolars. Harvard-MGH, AJP 6/02.

Bupropion Least Switching into Mania: In a 1-year study of 159 patients with bipolar I disorder or bipolar II disorder participated in a total of 228 acute (10-week) randomized trials of bupropion, sertraline, or venlafaxine as an adjunct to a mood stabilizer, full 7-day switches into hypomania and mania occurred in 11.4% and 7.9%, respectively, of the acute treatment trials and in 21.8% and 14.9%, respectively, of the continuation trials. The rate of threshold switches was higher in the 169 patients with bipolar I disorder (30.8%) than the 59 patients with bipolar II disorder (18.6%). Venlafaxine was associated with the highest relative risk of such switching and bupropion with the lowest. Risk of switch in mood polarity to hypomania or mania in patients with bipolar depression during acute and continuation trials of venlafaxine, sertraline, and bupropion as adjuncts to mood stabilizers. Leverich GS, et al. NIMH, Bethesda, MD 20892-1272. . Am J Psychiatry 2006 Feb;163(2):232-9. Ed: Other studies have found bupropion least likely to induce switching.  Since there was no control group, it is unclear how many would have switched without any anti-depressant.

Lamotrigine and Inositol Used for Treatment Resistant Bipolar Depression: In 66 patients with bipolar I or bipolar II disorder enrolled in the NIMH Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), all were in a current major depressive episode that was nonresponsive to a combination of adequate doses of established mood stabilizers plus at least one antidepressant. Patients were randomly assigned to open-label adjunctive treatment with lamotrigine, inositol, or risperidone for up to 16 weeks. The recovery rate with lamotrigine was 24%, whereas the recovery rates with inositol and risperidone were 17% and 5%, respectively. Treatment-Resistant Bipolar Depression: A STEP-BD Equipoise Randomized Effectiveness Trial of Antidepressant Augmentation With Lamotrigine, Inositol, or Risperidone. Nierenberg AA, et al. MGH Bipolar Clinic-Harvard. . Am J Psychiatry 2006 Feb;163(2):210-6. Ed: This is a very small and poor quality study, so it proves very little.

Fluoxetine + Atypical Better than Atypical in DB: Lilly DB PC study found 29% placebo (n=377), 40% olanzepine 5-20mg/d (n=370), and 56% fluoxetine 25-50 + olanzepine (n=86) reached remission in 8 weeks. MF Tohen, APA 5/03

Imipramine=Paroxetine with Low Lithium Except More Mania, Neither Helped if Lithium >0.8: DB PC 117 pt. all on lithium. For patients with high serum lithium levels (>0.8 mE/L), antidepressant response at endpoint also did not significantly differ from placebo. However, both paroxetine and imipramine were superior to placebo for patients with low serum lithium levels. Compared to imipramine, paroxetine resulted in a lower incidence of adverse events, most notably emergence of manic symptoms. Antidepressants may not be useful adjunctive therapy for bipolar depressed patients with high serum lithium levels. However, antidepressant therapy may be beneficial for patients who cannot tolerate high serum lithium levels or who have symptoms that are refractory to the antidepressant effects of lithium. Am J Psychiatry 2001 Jun;158(6):906-12, Emory U

Inositol Might Help: Bipolar Disord 2000 Mar;2(1):47-55. Small 22 patient DB PC study. 6 vs. 3 responders.

Maintain Anti-Depressants After Recovery from Depression: Usual guidelines for treating bipolar disorder recommend discontinuing antidepressants within six months of improvement. But UCLA found that patients treated under those guidelines were nearly twice as likely to relapse as those who continued taking antidepressants along with mood stabilizing medication for the first year after remission of acute bipolar depression. They also found no increased risk of manic relapse among study participants who continued the medication for a year. 84 bipolars whose depression symptoms eased with the addition of an antidepressant to an ongoing mood stabilizer. At one year after improvement of depression symptoms, 70 percent of the group that discontinued antidepressants had relapsed, compared to 36 percent of the continuation group. Mark Frye, AJP 7/03

MAOI Maybe OK for Refractory Bipolar Depression: 10 patients. Added to lithium or carbamazepine and no side-effects or impact on blood levels. 4 of 10 responded. J Clin Psychiatry 1995 Oct;56(10):471-5

Nefazodone Increases Carbamazepine Level: 12 men studied in lab test found nefazodone increased low dose of carbamazepine by 23%.Have been 2 reports of nefazodone causing carbamazepine toxicty. Laroudie, J Clin Psychoph 00;20:46, Paris

Quetiapine Did Well Compared to Placebo: In an 8-week DB PC study of 542 outpatients with bipolar I or II disorder experiencing a major depressive episode (DSM-IV), quetiapine (600 or 300 mg/day) at either dose was significant better on MADRS depression scores for a 50% response at 8 weeks : 58% and 57%, respectively, vs. 36% for placebo and remission (MADRS < or =12) were 53% vs. 28% for placebo. A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. Calabrese JR, et al. Case University, Cleveland, OH. . Am J Psychiatry. 2005 Jul;162(7):1351-60 and Trisha Suppes et al. Univ Texas Southwestern. J Clin Psychiatry 2005;6(suppl. 5)11-6. Ed: There was no comparison to using an anti-depressant. Quetiapine is extremely expensive and causes weight gain as well as diabetes. These researchers continue to push quetiapine as a favor to their manufacturer funding source, AstraZeneca. That's unethical, but it's true.

Topiramate = Bupropion in Very Small SB: In a small single-blind study of 36 depressed adults with bipolar I or II on divalproex and given topiramate (50-300 mg/day) or bupropion SR (100-400 mg/day) for 8 weeks, mean weight loss at endpoint was 1.2 kg in bupropion SR and 5.8 kg in topiramate. Response (>50% decrease in HAM-D) was topiramate (56%) and bupropion SR (59%). Baseline demographic and clinical parameters were comparable between the two treatment groups. The mean doses of study medication were 176 mg/day (SD = 102 mg/day) for the topiramate-treated group and 250 mg/day. Bipolar Disord 2002 Jun;4(3):207-13.  (Ed: Double-blind studies of psychiatric medication are definitely preferable to single-blind studies.)

Anti-Depressants Inducing Mania: A summary of eight studies suggests that lamotrigine (Calabrese, J Clin Psychiatry 60:79-88, 1999) and atypical anti-psychotics (Tohen, Arch Gen Psychiatry, 2003) do not induce mania, desipramine is the worst (Sachs, J Clin Psychiatry 55:391-3, 1994), that imipramine doesn't induce mania frequently but is worse than SSRIs (Cohn, Int Clin Psychopharm 3:313-22, 1989; Nemeroff, Am J Psychiatry 158:906-12, 2001; Silverstone, Acta Psychiatr Scand 104:104-9, 2001), and that SSRIs, bupropion, and venlafaxine are all about the same (Post, Bipolar Disord 3:259, 2001). Ed: Calabrese works closely with the manufacturer of lamotrigine.