The Last Psychiatrist, July 5, 2005

Do Antidepressants Induce Mania?

No.

This myth is the result of imprecise use of language. Many2 3 4 5 6 have detected a temporal association between the use of tricyclic antidepressants and episodes of mania in patients with bipolar disorder, though no plausible mechanism has been suggested, much less found. It has been assumed that this association could be extended to all antidepressants despite their substantial chemical and pharmacological heterogeneity. However, such an association between mania and selective serotonin reuptake inhibitors has not been found. In fact, the studies 7 8 9 which have been done strongly indicate that the rate of mania with SSRIs is no different than the normal switch rate of bipolar disorder. A recent study10 11 of venlafaxine, sertraline and bupropion found a 13% 10 week switch rate into mania or hypomania (excludes symptoms lasting less than 7 days), and an 18% one year switch rate, but this study was confounded by the concomitant use of mood stabilizers of dubious efficacy (lamotrigine, gabapentin, topiramate) in 22% of the patients, and the lack of a placebo arm to establish the baseline switch rate. Because of the significant phenomenological heterogeneity of the patients with “bipolar disorder” in clinical trials, a placebo arm is vital in order to compare results in different studies.

It must be reiterated that these are studies of temporal associations between mania and antidepressants, and no causal link can be inferred. Despite this, many continue to discuss the question in terms of the induction of mania by antidepressants. This betrays a bias that is supported neither by data nor logic. For example, studies of novel antidepressants cite rates of “induced” mania, while studies of antiepileptics discuss “breakthrough” manias, automatically presupposing a difference in the mechanism of mania. Similarly, it is popularly assumed that bupropion is less likely to induce mania than SSRIs. This assumption is formalized in the Expert Consensus Guidelines 200012, where bupropion “was clearly rated as the antidepressant least likely to precipitate an episode of mania.” It is not immediately obvious why this was so clear, as there is virtually no evidence indicating this. One single study13 (N=19) found bupropion to be less likely to induce a switch than desipramine. The final results of Post, above, are still pending, but it appears evident that if one has decided to accept the myth that antidepressants induce mania, there is no reason to believe bupropion is any less likely to do this.

The accumulated data in the field strongly suggest that the real risk in the treatment of bipolar depression is ineffectiveness, not mania.

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2 Prien RF. Klett CJ. Caffey EM Jr. Lithium carbonate and imipramine in prevention of affective episodes. A comparison in recurrent affective illness. Arch Gen Psych 29(3):420-5, 1973 Sep.

3 Prien RF. Kupfer DJ. Mansky PA. Small JG. Tuason VB. Voss CB. Johnson WE. Drug therapy in the prevention of recurrences in unipolar and bipolar affective disorders. Report of the NIMH Collaborative Study Group comparing lithium carbonate, imipramine, and a lithium carbonate-imipramine combination. Arch Gen Psych 41(11):1096-104, 1984 Nov.

4 Boerlin HL. Gitlin MJ. Zoellner LA. Hammen CL. Bipolar depression and antidepressant-induced mania: a naturalistic study. J Clinical Psychiatry. 59(7):374-9, 1998 Jul.

5 Wehr TA. Goodwin FK. Rapid cycling in manic-depressives induced by tricyclic antidepressants. Arch Gen Psychiatry. 36(5):555-9, 1979 May.

6 Jann MW. Bitar AH. Rao A. Lithium prophylaxis of tricyclic-antidepressant-induced mania in bipolar patients. Am J Psychiatry. 139(5):683-4, 1982 May.

7 Amsterdam JD. Garcia-Espana F. Fawcett J. Quitkin FM. Reimherr FW. Rosenbaum JF. Schweizer E. Beasley C. Efficacy and safety of fluoxetine in treating bipolar II major depressive episode. Journal of Clinical Psychopharmacology. 18(6):435-40, 1998 Dec.

8 Peet M. Induction of mania with selective serotonin re-uptake inhibitors and tricyclic antidepressants. British J Psychiatry. 164(4):549-50, 1994 Apr.

9 Nemeroff CB, Evans DL, Gyulai L, Sachs GS, Bowden CL, Gergel IP et al. Double-blind, placebo-controlled comparison of imipramine and paroxetine in the treatment of bipolar depression. Am J Psychiatry 2001; 158:906-12.

10 Post RM. Altshuler LL. Frye MA. Suppes T. Rush AJ. Keck PE Jr. McElroy SL. Denicoff KD. Leverich GS. Kupka R. Nolen WA. Rate of switch in bipolar patients prospectively treated with second-generation antidepressants as augmentation to mood stabilizers. [Clinical Trial. Journal Article. Randomized Controlled Trial] Bipolar Disorders. 3(5):259-65, 2001 Oct.

11 Post RM. Leverich GS. Altshuler LL. Frye MA. Suppes TM. Keck PE Jr. McElroy SL. Kupka R. Nolen WA. Grunze H. Walden J. An overview of recent findings of the Stanley Foundation Bipolar Network (Part I). [Journal Article. Review. Review, Tutorial] Bipolar Disorders. 5(5):310-9, 2003 Oct.

12 Sachs GS. Printz DJ. Kahn DA. Carpenter D. Docherty JP. The Expert Consensus Guideline Series: Medication Treatment of Bipolar Disorder 2000. Postgraduate Medicine. Spec No:1-104, 2000 Apr.

13 Sachs GS. Lafer B. Stoll AL. Banov M. Thibault AB. Tohen M. Rosenbaum JF. A double-blind trial of bupropion versus desipramine for bipolar depression. J Clin Psych 55(9):391-3, 1994 Sep.

See also: Bipolar Controversoies

Bipolar

From The Last Psychiatrist - April 29, 2008
Experts Weigh In On Bipolar Disorder

And they conclude there's a lot of bad information out there. They try to set the record straight.

From the article:

[The Diagnostic Guidelines Task Force of the International Society for Bipolar Disorder (ISBD)] chairman S. Nassir Ghaemi, MD, MPH ... brought together some of the world's clinical experts on bipolar disorder and key researchers with the goal of having them develop a more systematic and coherent set of diagnostic guidelines.

In other words, what do the best minds in psychiatry have to say about bipolar disorder? What says the latest data?


Also expanded was the definition of bipolar depression, according to Ghaemi. "It is not just depression in someone who happens to have had manic episodes but rather specific kinds of depression with specific features," he said.

...Clinical features include early onset of first depression (before age 25 years), multiple (5 or more) previous episodes of depression, family history of bipolar disorder, atypical depressive symptoms (such as leaden paralysis), psychomotor retardation, psychotic features, and/or pathological guilt.

That's based on the PET scans and the NIMH genetic studies which have so far cost a quadrillion dollars, right? Well, here's a line from the actual Guidelines. It's the kind of line that makes you, well, look upon the works, and despair:

The subgroup describes this as a 'probabilistic' approach to the differentiation of bipolar from unipolar depression, and offers a heuristic of operationalized criteria to be studied empirically. Areas of dissensus persist...


Got that? No? Good, it'll go down easier. So it's soon to be official: Farewell, Depression.

What else does the team think? Oh: schizoaffective disorder doesn't exist.

Most of the evidence, he explained, suggests that schizoaffective disorder does not represent a separate categorical disease entity; rather, it is "a variation on schizophrenia or a variation on mood disorder or co-occurrence of the two." The subgroup recommended dropping the schizoaffective disorder diagnostic category altogether from DSM-V...

The question is, if the evidence has so far been indicating that schizoaffective is not real, why did we have to wait for the DSM to tell us it doesn't exist? Why can't psychiatry simply make it happen?

But the sleight of hand is saying that the schizoaffective is "really" a variation on a mood disorder (read: bipolar.) It is equally plausible that bipolar disorder is a variation of schizoaffective disorder since neither one exist except synthetically. I don't mean the symptomatology doesn't exist, I mean the classification is completely empty. We choose to call this thing schizoaffective, and now we choose not to. We chose to call it depression, now we choose to call it bipolar depression. It's not like you chose to call it a unicorn but later discover it's actually a rhinoceros. A more accurate analogy is that you chose to call this a unicorn, and now choose to call it a ki-ran. Wait-- what's a ki-ran, you say? Exactly.

Or, you find an elephant's leg, and say, this is an elephant. And next you find a horse's leg, so you say, this has much in common with an "elephant," same joint here, so this is an elephant also. Which would be okay, except then we start making treatment decisions based on that logic: ah ha! Antifungal cream is the mainstay of treatment for all elephant illnesses! And meanwhile the elephant dies of throat cancer. Does it make any sense that the best of our science suggests that the manipulation of four neurotransmitters is somehow involved in the treatment of every single psychiatric illness known, from anxiety to xenophobia?


What do we say to all of those patients diagnosed with schizoaffective disorder? Oops? Is it any consolation to them, or their families, to hear that it's actually bipolar? How about the criminal cases of schizoaffectives? Should they get new trials? Their new diagnosis of bipolar has more studies to draw from, it has more play in the legal system, and better known to jurors?

As a final question, Ghaemi was asked if he believed bipolar disorder is being overdiagnosed. "While unipolar depression, personality disorders, and schizophrenia have each had periods of overdiagnosis, there has never been an era in which bipolar disorder has been overdiagnosed," he said, "no matter what skeptics claim."

He said that concerns about bipolar overdiagnosis are largely anecdotal, have not been empirically well-established, and ignore solid evidence of continued underdiagnosis.

And there's some more sleight of hand. Empirically? What's the test to see if it is actually bipolar or actually depression? Especially when you have the power to change definitions?

The best is at the end:

The lack of focus on bipolar disorder has led to neglect and controversy, Ghaemi noted. "Our task force," he said, "is a step toward more consensus and less controversy."

Bipolar is the neglected diagnosis? And this will cause less controversy? Are you serious?