Sunday, June 12, 2011

Akiskal and the Bipolar Spectrum

In the last post, we learned that the Editor-in-Chief of the Journal of Affective Disorders has published 165 papers in the journal, 155 of these since becoming editor in 1996. Excluding commentaries and editorials, that makes for a grand total of 142 articles thus far during his tenure as editor.

The two major themes of Dr. Hagop Akiskal's papers are (1) the bipolar spectrum, and (2) temperament as the basis of mood, behavior and personality (e.g., Lara et al., 2006). Clearly, I cannot begin to summarize the content of these papers, but I will give some background material on the bipolar spectrum and "soft" bipolar (Akiskal & Pinto, 1999 - not published in JAD).

Bipolar disorder, one of the most serious mental illnesses, is marked by periodic bouts of depression and mania (Bipolar I) or by depression and hypomania (Bipolar II). Given that depression often presents as the initial polarity, bipolar is frequently misdiagnosed as major depressive disorder (MDD), with disastrous consequences.1 The rigid categories of DSM-IV, however, may not capture everyone who displays clinically significant symptoms of bipolar disorder. Ghaemi et al. (2002) have noted that:
...limitations of the DSM-IV nosology may impede the diagnosis of BD, because the DSM-IV has rather broad criteria for MDD and narrow criteria for BD.
According to Akiskal and Pinto, the evolving bipolar spectrum (circa 1999) includes:



BIPOLAR II½: CYCLOTHYMIC DEPRESSIONS [often labeled as borderline personality disorder]



BIPOLAR IV: HYPERTHYMIC DEPRESSION - "patients with clinical depression that occurs later in life and superimposed on a lifelong hyperthymic temperament."
Each of the diagnostic categories was illustrated by a clinical case report. Cyclothymia is included in DSM-IV: "A history of hypomanic episodes with periods of depression that do not meet criteria for major depressive episodes. There is a low-grade cycling of mood which appears to the observer as a personality trait, and interferes with functioning." Hyperthymia, however, is not a diagnosis but an affective temperament "characterized by exuberant, upbeat, overenergetic, and overconfident lifelong traits." More specifically (Akiskal & Pinto, 1999):
The attributes of a hyperthymic temperament are not episode-bound and constitute part of the habitual long-term functioning of the individual. Patients are typically men in their 50s whose lifelong drive, ambition, high energy, confidence, and extroverted interpersonal skills helped them to advance in life, to achieve successes in a variety of business domains or political life.
Arnold Schwarzenegger comes to mind [if he had started having depressive episodes several years ago]. In fact, the case study of bipolar IV was presented as a highly successful, 53 year old married lawyer with three other families in different countries.

Do powerful, philandering, middle-aged men who become depressed in their 50s really need their own special diagnosis??

There are critics, of course... In his critique of the spectrum, Paris (2009) called it "bipolar imperialism" and said: "Until further research clarifies the boundaries of bipolarity, we should be conservative about extending its scope." It seems that no one is safe any more. Recurrent depression? Bipolar. Anxious and depressed? Most certainly bipolar.

But the worst frontier of all has to be Bipolar Type VI: Dementia (Ng et al., 2008). This paper presents "selected" case histories of 10 elderly patients from the California/Mexico border and Brazil. These patients presented with "late-onset mood and related behavioral symptomatology and cognitive decline without past history of clear-cut bipolar disorder." In other words: dementia (caused by neurodegenerative disease), with classic symptoms such as:
  • Having hallucinations, arguments, striking out, and violent behavior

  • Having delusions, depression, agitation

Are we surprised that mood stabilizers and atypical antipsychotics were said to be beneficial??

click on image for a larger view

Adapted from Table 1 (Ng et al., 2008). Clinical features and response to treatment in elderly patients with bipolar disorder type VI. [NOTE from The Neurocritic: atypical antipsychotics are in red, mood stabilizers are in blue.]

Cases 1-5 are poor elderly Latino patients attending an adult day treatment center, and cases 6-10 are from private practice in a more affluent area of Brazil. Galantamine, donepezil, and rivastigmine are acetylcholinesterase inhibitors typically used to treat Alzheimer's disease [with limited effectiveness], while memantine blocks NMDA glutamate receptors. So why would the authors claim that the mood and behavioral problems had anything to do with bipolar disorder?

Omitted from Table 1 (for space reasons and ease of presentation) are columns for premorbid temperament (as judged by family members) and family history. The temperaments were mostly cyclothymic or hyperthymic. Family histories included none (n=3), mood & anxiety (n=2), alcohol (n=2), and bipolar disorder (n=3). OK then, only 3 of the 10 patients had a family history of bipolar disorder. Again, what's the rationale for creating the new category of "bipolar type VI"?
We present our perspective as an alternative to the more commonly held clinical–neurological view that agitation, impulsivity and related mood instability in Alzheimer's and other dementia patients merely represents frontal lobe dysfunction (Senanarong et al., 2004). A more sophisticated view in the literature argues that behavioral–cognitive syndrome in Alzheimer's disease is a prodromal stage, whereas in fronto-temperal dementia the behavioral disorder appears when the cognitive deficit is relatively mild (Jenner et al., 2006). Our perspective, while ostensibly recognizing the dementia setting postulates the possible contribution of pre-existing familial and/or temperamental diathesis for bipolarity in patients presenting with dementia-like clinical pictures with marked mood and behavioral disturbances.
Are they grasping at straws to justify prescribing mood stabilizers and atypical antipsychotics to these patients, perhaps? Let's look at the declared Conflicts of Interest of the senior author on this paper:
Dr. Akiskal is on the US GSK Advisory Board, Abbott's Latin American Bipolar Advisory Board, and International Advisor to Sanofi-Aventis. He has received honoraria for lectures from these companies, as well as from Lilly.
Branded formulations of generic valproic acid, one of the most common mood stabilizers, include:
  • Depakene (Abbott Laboratories in U.S. & Canada)
  • Depakine (Sanofi Aventis French)
  • Depakine (Sanofi Synthelabo Romania)
  • Deprakine (Sanofi Aventis Finland)
  • Epival (Abbott Laboratories U.S. & Canada)
  • Epilim (Sanofi Synthelabo Australia)
  • Valcote (Abbott Laboratories Argentina)
GSK products include two other mood stabilizers, Lamictal (lamotrigine, given to six of the patients) and Keppra (levetiracetam). Besides the antidepressants Prozac and Cymbalta, which are thought to be bad for bipolar spectrum patients, Lilly manufactures Zyprexa (olanazpine), the atypical prescribed to three of the patients.

However, it appears that all Conflicts of Interest might not have been declared in the JAD paper. Three additional pharmaceutical companies were mentioned in a 2010 American Journal of Psychiatry article:
Dr. Akiskal has served on speakers or advisory boards for Abbott, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, and Janssen.
AstraZeneca makes Seroquel (quetiapine), an atypical prescribed to five patients, Bristol-Myers Squibb makes Abilify (aripiprazole), an atypical that was not given to any of the patients, and Janssen's products include Risperdal (risperidone), an atypical prescribed to one patient.

For a summary of the well-publicized scandal that atypical antipsychotics are overprescribed to elderly patients as a means of behavioral control, see Drugging the Vulnerable: Atypical Antipsychotics in Children and the Elderly:
In nursing homes, 14% of residents have been given at least one prescription for a second-generation antipsychotic, according to a government investigation. A full 88% of these prescriptions are given to people with dementia, despite the fact that these drugs may double the risk of death in these patients (there is a black box warning on the drug to this effect). The investigation estimated that $116 million Medicare dollars have been spent filling antipsychotic prescriptions that never should have been written.
If these elderly patients were diagnosed with the official label of Bipolar Disorder Type VI, then the prescriptions could potentially be justified, and an old discredited market becomes new once again.


1 Antidepressants can trigger mania or hypomania.


Akiskal, H.; Pinto, O. (1999). THE EVOLVING BIPOLAR SPECTRUM Prototypes I, II, III, and IV. Psychiatric Clinics of North America, 22 (3), 517-534 DOI: 10.1016/S0193-953X(05)70093-9

Ghaemi SN, Ko JY, Goodwin FK. (2002). "Cade's disease" and beyond: misdiagnosis, antidepressant use, and a proposed definition for bipolar spectrum disorder. Can J Psychiatry 47:125-34.

Lara DR, Pinto O, Akiskal K, Akiskal HS. (2006). Toward an integrative model of the spectrum of mood, behavioral and personality disorders based on fear and anger traits: I. Clinical implications. J Affect Disord. 94(1-3):67-87.

Ng, B., Camacho, A., Lara, D., Brunstein, M., Pinto, O., & Akiskal, H. (2008). A case series on the hypothesized connection between dementia and bipolar spectrum disorders: Bipolar type VI? Journal of Affective Disorders, 107 (1-3), 307-315 DOI: 10.1016/j.jad.2007.08.018

Paris J. (2009). The bipolar spectrum: a critical perspective. Harv Rev Psychiatry 17:206-13.

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At June 13, 2011 5:37 AM, Anonymous Anonymous said...

There is really only one true bipolar disorder and that is Bipolar I. The rest of the "bipolar spectrum" nonsense is complete BULLSHIT.

At June 13, 2011 10:17 AM, Blogger Bernard Carroll said...

I think Anonymous takes too strong a position. I have long been partial to Jules Angst’s proposal – that there is severe or mild depression (D or d) as well as severe or mild mania (M or m) and that any given patient may display some combination of these, i.e. DM (bipolar I) or dM (another form of bipolar I) or Dm (bipolar II) or dm (cyclothymia). Then there are a few patients with just M (so-called unipolar mania) and a lot of patients with just D (unipolar depression). I leave it to others to decide about cases that display just d or m. As Kraepelin said, the manifestations of manic depressive illness show infinite gradations, merging imperceptibly from clinical episodes into temperament.

Keep in mind that the commonest psychiatric disorder in the families of bipolar probands is D, unipolar depression. And, as Kraepelin taught us a century ago, there are also mixed manic-depressive states. One of my memorable mixed MD patients, pacing the ward and wringing his hands in agitation asked me didn’t I think his depression was the absolute worst depression in the entire history of the world! The admixture of painful depressed mood with grandiosity was striking.

The very existence of mixed states tells us that separate circuits mediate distinct components of affective disturbance, and that these components are orthogonal. A neurodegenerative process may release depressive or manic symptoms and behaviors by knocking out the modulation of these circuits, but Occam’s razor requires that we refrain from metaphysical speculations like Ng et al’s suggestion that the dementia “released latent bipolarity.” You might just as well say that when patients with early dementia start shoplifting and swearing and hitting people they are displaying latent sociopathy.

Here is more on the topic of brain mechanisms in manic-depression.

At June 14, 2011 10:06 PM, Anonymous Anonymous said...

You should go to the Presidio library tomorrow night to hear about Bipolar IN Order

At June 14, 2011 10:23 PM, Blogger The Neurocritic said...

I believe that last comment was from someone affiliated with Bipolar Advantage, which is located in Tiburon, CA {the IP address was from neighboring Mill Valley, CA}.

At June 14, 2011 10:27 PM, Blogger The Neurocritic said...

Dr. Carroll - Thanks for your comment. The part about "latent sociopathy" was very amusing...

At June 15, 2011 6:48 AM, Anonymous Murfomurf said...

Surely anyone familiar with the psychological characteristics of human beings would have observed that most traits or mental disturbances occur on continua. Rarely is an individual so simple that they have just one aspect to any unusual thinking or behaviour, but likely a combination of differing strengths of several from the possible spectrum. My preference is to have just one category: 'Mood disorder' with everything else, whether mania, depression or psychotic aspects, added as 'features'. Then we can cut down on labeling (and writing about the labels with examples) and concentrate on individuals suffering their own species of mood disorder, so we can work out strategies to deal with the symptoms which are most disabling.

At June 15, 2011 11:25 AM, OpenID omnologos said...

is one's proliferation of papers in one's own journal a sign of Bipolar I perhaps?

At June 17, 2011 12:44 PM, Anonymous Don Klein said...

I almost always agree with Carroll and Angst but here think they may be over simplifying in that D is dividable into Endogenomorphic (SSRI,TCA,ECT) responsive and Atypical(MAOI responsive--not SSRI,TCA,ECT responsive--if adolescent onset--as I think Barney has contemplated previously--and probably Mania comes in discrete forms
Where classic Bipolar I (lithium responsive) vs others with a whole variety of complex partial seizure symptom
manifestations often do better on anti-convulsants--though this is personal opinion and not well documented.
This certainly agrees with Barney's point about independent regulators re mood,energy,appetitive and consummatory hedonics.
Don Klein

At June 17, 2011 1:11 PM, Blogger Bernard Carroll said...

Thanks for weighing in, Don. I agree with you on the heterogeneity of clinical depressions, and I should have made it clear that the D and d concept that I picked up from Jules Angst applies to the endogenomorphic domain.

At January 31, 2013 1:39 AM, Anonymous bipolar said...

I havae rapid cycling bipolar I. IMHO drugs as Zyprexa should only be given to patients that are actually psychotic or at least bordering mania.

Living with these drugs is not easy and there are serious side effects for most patients. There must be a serious problem before these drugs are even considered and there must be strong benefits to keep using them. That said, Zyprexa etc, has been a life saver for me. It is truly an amazing drug.

Furthermore, I strongly dislike that young people with relatively normal problems in life are diagnosed at all with anything but "find a grownup to talk to". Giving them anti-psychotics is very, very wrong.

Doctors that prescribe anti-psychotics should be forced to try them to see the effects they have on normal people, or indeed bipolar patients that are low.

Ask anybody with true bipolar disorder and they can explain the difference. When manic these meds make you virtually normal. When normal these meds make you a zombie.

At August 15, 2014 8:52 AM, Anonymous John Cenas said...

What if industry invites Akiskal because of his writings and not otherwise?
Please consider that any field in human medicine nowadays has industry support and i'm not saying that's a good thing or the only way but that's the American way. Don't forget although that URSS reached space first.

At September 10, 2017 12:16 PM, Anonymous Chris Aiken, M.D. said...

There is some misunderstanding of Akiskal's papers here. Most of them argue that psychiatric medications should be minimized for the affective temperaments (also called bipolar spectrum or soft bipolarity). He consistently advocates for psychotherapy as the best approach to temperament, and makes humanistic arguments that psychiatrists should "respect" the patients temperament to avoid "aggressive" over-medication.

He does suggest that temperament can help inform the choice of medication if it is used, but most of his papers focus on psychosocial areas like career counseling for people with affective temperaments rather than medication. His view is that affective temperaments can help doctors understand the person behind the diagnosis, as well as the genetics behind bipolar and depression.

Most academic psychiatrists have relationships with the pharmaceutical industry, and Hagop Akiskal is one of the few among them who has not traveled extensively to give paid talks for the pharmaceutical industry.


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