Updating the model of bipolar disorder:

Where we were, are, and hope to be.

Jack E. Rosenblatt, M.D.                                                                                          (Editor, Pharmacotherapy in Psychiatry)

We have received variable (and sometimes conflicting) communications from colleagues about optimal, evidence-based treatment of bipolar disorder (and about bipolar depression, particularly), with respect to whether antidepressants have a role beyond treatment of a small subgroup that may not respond to anything else. The literature is not without documentation of both the effectiveness and tolerability of antidepressants for some patients and the outweighing of benefit by risk of antidepressant-emergent mood conversion to  mania in remitted patients or worsening of extant mania spectrum symptoms in unremitted patients.

   Until  1980, when the concept of bipolar II disorder had been developed and was being promulgated and reacted to, antidepressants were the principal treatment for bipolar depression (coadministered with a drug conveying antimanic activity, now called a “mood stabilizer,” for continuing prophylaxis of mania spectrum symptoms at the frequency reported naturalistically or historically for their patients and/or to suppress what many believe to represent antidepressant-induced mood conversion to mania spectrum symptoms), .

Clozapine was then the sole atypical neuroleptic available, but its bone marrow-suppressive effects made normative usage in bipolar and other disorders infeasible. First-generation neuroleptics were still being implicated in tardive dyskinesia and neuroleptic malignant syndrome at higher rates than currently reported,  so they, too, had no credible future as standard treatment for bipolar depression. Lamotrigine was a drug of unknown therapeutic potential for bipolar depression, and what we knew at that time about lithium, carbamazepine, and valproic acid suggested (as it does still) that they might afford no more than moderate, transient efficacy for acute bipolar depression when they afforded help at all.

The sole pharmacotherapeutic option available at the time that seemed to offer the prospect of more consisted of the standard tricyclic antidepressants, the heterocyclics amoxapine (with its potent D2-antagonist metabolite), maprotiline, and trazodone, and the monoamine oxidase inhibitors, and prescribing them was tantamount to a moral imperative for physicians of desperately suicidal patients who had proved insufficiently responsive to mood stabilizers alone or electroconvulsive therapy. We knew the increment of risk of completed suicide in bipolar disorder, relative to rates in the general population and in persons with some other psychiatric disorders, and at that time had the benefit of no published findings corroborating the activity of lithium or clozapine to reduce it.

The  1970s and early 1980s proffered a Hobson’s Choice (of no rational preferment) apropos of a generally recommended protocol other than electroconvulsive therapy for acute and prophylactic treatment for persons with bipolar disorder who were manifesting and  suffering from a major depressive episode. Yet, even when patients, families, colleagues, and the general public had been persuaded to consent to it by credible evidence of efficacy, tolerability, and safety, they proceeded, understandably,  with no better than aggrieved acceptance for reasons of cost, inconvenience, and stigma. That the intracranial stimulation (electroconvulsive therapy or milder, differently patterned electric stimuli introduced later was (and is) typically recommended with adjunctive pharmacotherapy (sometimes the same as that that had as monotherapy or polytherapy proved equivocally beneficial or ineffective)  seems in retrospect (and still in real time in some quarters)  reflective of the trammeled judgment that controversy pressed into formulations of recommended practice. Anecdotal experience, expressed and summed by self-designated and in some cases, authentic experts, seemed so far ahead of systematic evidence that the margin made the field jittery in  advocacy. A stubborn status quo of weak checks and balances continued, anchored by a weight of added evidence too light to make a difference. Intracranial stimulation of any intensity was always a shot in the dark, and at this point seems to have gone as far as it can, methodologically for the moment. and therefore intellectually, and the field must again acknowledge having reached a point of awkward counterpoise between what is done and what is known  (historically, a focus of more magnified scrutiny in psychiatry than other areas of medical specialization, whose black bags have never accommodated a leukotomy knife).)

In the event, some experienced psychiatrists recommended doing what should already have been done: optimizing mood stabilization with mood-stabilizing drugs. Which was a wonderful clue when it proved effective: a proportion of patients presenting with what was presumed by them, their families, or generalists to be “depression” was the depressive mixed state (a diagnosis applied to a person who meets guild diagnostic criteria for major depression and additionally evinces two or more core symptoms of mania (or hypomania, depending upon severity). Investigations of bipolar depression over the last thirty years have reported increasing proportions of persons with “pure” bipolar depression who instead have mixed syndromes (depression plus hypomania or mania), with the most recent entries requiring almost no subaudition in the reading: persons with bipolar depression are persons with hypomania or mania who are no longer or have not been manifesting elation or euphoriousness).

The features of mixed states collectively make the case for non-necessity of causality apropos of what has been conceptualized causally as antidepressant-induced mood-switching to hypomania or mania,  Consider them: mixed states occurring with a distribution of dysphoria and elation/euphoria after remission of three-to-one (when making an evidence-based assumption that a significant proportion of bipolar depressive symptoms are tantamount to dysphoria); significant (and among the strongest correlates of antidepressant-induced mood-switching) reported to be lifetime number of mania spectrum symptom episodes before onset of putative antidepressant-induced mood-switching;  severity of symptoms; suicide attempts; severity, frequency of hypomanic or manic episodes, worsening of manic or hypomanic symptoms during treatment with antidepressants of all classes; improvement during treatment with neuroleptics of all classes. Mood change (to elation or  euphoriousness) from dysphoria, or the spectrum upon which exist sleep disturbance, irritability, frustration, tension, and/or anger or rage). Patients with depressive mixed states present or are presented for treatment when symptom-related behaviors escape control and convey risk of harm to self or others.

Dysphoria, indicate our treatment studies, improves during treatment with neuroleptics and lithium, and perhaps some antiepileptic medications, such as valproic acid, the latter coadministered with antidepressants to suppress or mitigate dysphoria. Antidepressants do not appear to prevent benefit of mood stabilizing drugs, and may have effects similar to those in persons without bipolar disorder, when persons with bipolar disorder experience core symptoms of depression (sadness, sad cognitions, drive disturbances (diminution), sleep disturbance, reduced motivation, fatigue, and, perhaps most specifically characteristic, anhedonia, a reduced experience of pleasure or spontaneous pleasurable sensation or cognition). Persons who are dysphoric can simultaneously or in close contemporaneity experience depressive symptoms; so too elation or euphoriousness.

Persons with bipolar disorder, therefore, may or may not have depressive comorbidity, whereas they manifest and experience dysphoria as a characteristic and defining feature of bipolar disorder (a misnomer, after all, because if there are different “poles,” they are elation/euphoria and dysphoria). So then, according to recent evidence as it reads, there exists a mood dysregulation disorder that some (most) still call bipolar disorder, and it may or may not be comorbid with depressive symptoms. Severity is a function of frequency of change (from elation/euphoria to dysphoria and back) and magnitude of affects changed from and to. Persons who have comorbid disorders are sicker, more complex in the treatment, and more guarded in their outcomes, and that includes comorbid depression (distinct from core dysphoria).

Do antidepressants induce mood-cycling to hypomania or mania? Causality need not exist logically between exposure to antidepressants followed by onset of manic spectrum symptoms. Persons with elation and dysphoria have both, and one or the other or both are typically more severe when hospitalization has become indicated (for a variety of exogenous as well as endogenous catastrophe). If dysphoria is diagnosed as depression, it becomes more likely that an antidepressant will be prescribed, whereafter it continues no less likely that mood will remain changeable between elation and dysphoria. (Persons with reason to be in hospital are, like others, less likely to have reason for elation, as they remain dysphoric. When they manifest elation or dysphoria after starting antidepressants, no logic confines causality to antidepressants (which withal may intensify elation or dysphoria).) Elation or euphoria revert to prehospitalization quality and frequency after “stress” diminishes, but no reason dictates causal agency of antidepressants.).

A new DSM may (should) eliminate “bipolar disorder” (as it once did “manic depressive reaction”) and substitute, ” Mood dysregulation disorder.” The latter may sometimes be comorbid with depressive symptoms and should so state, with the latter understood as not integral to the mood dysregulation disorder.

Antidepressants are effective for core symptoms of depression and may exacerbate symptoms of mood dysregulation if given as monotherapy. When indicated for comorbid depression, they should be coadministered with a mood stabilizing drug (neuroleptics, lithium, some of the anticonvulsants), which also are independently effective for mood dysregulation symptoms.

The nosology for depression need contain no more than “depressive disorder” and may or may not be comorbid with mood dysregulation disorder. Because antidepressants may worsen mood dysregulation symptoms, a specified “comorbid with” would advert clinicians to that diathesis.

(Our preferences for diagnostic and therapeutic change of bipolar and unipolar affective disorders)

Then: Bipolar disorder (types I and II, mania, depressive, mixed)

Now: Mood dysregulation disorder (no subtypes)

Then: (Colloquial) “Bipolar depression” (depressive phase of bipolar disorder)

Now: Mood dysregulation disorder with comorbid depressive disorder

Then: Depressive disorder treated with antidepressants

Now: Depressive disorder treated with antidepressants. (When comorbid with mood dysregulation disorder, depression is treated with antidepressant coadministered with mood stabilizer.)

Then: Mania treated with mood stabilizer (neuroleptic, lithium, valproic acid for males and nonfertile women of childbearing age; women not of childbearing age; carbamazepine to be avoided because of induction of drug metabolism and unstable or low steady-state concentrations of mood stabilizer

Now: Clinically significant mood dysregulation treated with mood stabilizer. Comorbid depression can be treated with antidepressant if coadministered with mood stabilizer; comorbid anxiety spectrum disorder treated with anxiolytic; antidepressant coadministered with mood stabilizer. (Generally, comorbid disorders treated as if independently occurring except for coadministration with mood stabilizer as necessary to prevent or mitigate worsening of mood dysregulation).


Reduced use of lithium because of nephrotoxicity associated with continuous exposure of ten years or longer; continuing specialized use of lithium in patients with consistently or severely elevated suicide risk; increasing use of neuroleptics for antimanic (tantamount to mood stabilizing) activity; increasing use of long-acting injectable for improved compliance and enhanced prophylaxis. Development of long-acting injectable formulations for extrapyramidal adverse effects. Increased acceptance of and acknowledgment of polytherapy as normative. Increased emphasis on pharmacokinetic drug-drug interactivity because of bioavailability-related adverse effects and increasing use of polytherapy for enhanced mood stabilization. Increased use of antidepressants prescribed selectively for depressive symptoms (avoidance of exposure in patients with acute dysphoria or mood dysregulation); generalized anxiety; panic disorder; obsessive-compulsive disorder; increasing use of orally administered pharmacotherapy in children and adolescents; expanded evidence base on drug clearance during monotherapy and polytherapy, with increased emphasis on active metabolites, prodrugs, pharmacogenetics. Increased evidence on effects of prescribing on acute and prophylactic effects of mood stabilizers; resurgence of informed prn dosing for fine-tuning drug effects. Beginning of use of long-acting opioids with low abuse potential, prescribed for depression and chronic pain

Adoption of new nosology pursuant to changing model of bipolar disorder to mood dysregulation disorder with comorbidities. Continuing development of mutually moderated states and traits; exploration of drug effects on both. Addition of standardized curriculum of clinical pharmacology during psychiatric residency. Addition of clinical pharmacology segment to Board examination in psychiatry.








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