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 I: FULL-BLOWN MANIA

BIPOLAR I½: DEPRESSION WITH PROTRACTED HYPOMANIA

BIPOLAR II: DEPRESSION WITH HYPOMANIA

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

BIPOLAR III: ANTIDEPRESSANT-ASSOCIATED HYPOMANIA

BIPOLAR III½: BIPOLARITY MASKED—AND UNMASKED—BY STIMULANT ABUSE

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.


Footnote

¹ Antidepressants can trigger mania or hypomania.

References

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.