A masterpiece paper on “bipolar disorder” 10.0

“The primacy of mania: a reconsideration of mood disorders,”2 published in 2009 by Ghaemi et. al. was referred to as “A masterpiece paper on “bipolar disorder.”  by Michele Fornaro et.al.1 in 2012. 

Even though Fornaro et.al. use the terminology “bipolar disorder,” I believe they are actually referring to the original disease concept of Manic Depressive Illness (MDI), of which “bipolar” is a smaller subset. Kreapelin’s  original MDI disease concept of a century ago, comprises predominantly mixed mood states, 60%,  with pure severe depression and pure mania constituting 20% each. This disease framework, which has not been disproven in subsequent “modern” studies, was disassembled in the 1980 DSM-III and the historical understanding of what constitutes “mania” was lost; and by default every mood state then became some form of “depression.” As Ghaemi et. al. explain, this had led to an inappropriate focus on antidepressant treatments and inattention to second-messenger modifiers of lithium, valproic acid, and carbamazepine (aka “mood stabilizers”). 

As shown below, the way in which Koukopoulos and Ghaemi define mania in a historical context goes far beyond the elation and euphoria routinely associated with today’s mania. Additionally, their definition implies treatment approaches contrary to commonly accepted standards. 

The current dilemma for clinical practice is that psychiatrists are not trained to elicit milder degrees of non-euphoric psychomotor excitation/agitation when evaluating a patient. I frequently see in charts: “no manic symptoms reported” (usually meaning no elation, euphoria, or profligate spending), and that is the sum total of the doctor’s assessment of mania. Many psychiatrists will then think that any patient who is not blatantly euphoric or elated is therefore depressed and needs an antidepressant.

For additional background on these authors:

Athanasios  Koukopoulos (1931-2013), a psychiatrist who practiced in Rome from 1963-1998, is considered to be one of the most innovative thinkers in the field of psychiatry in the late 20th and early 21st century with his “primacy of mania theory” and is better known in Europe than in the U.S. for his work. His death was a major loss for the field.  

Nassir Ghaemi is the Director of the Mood Disorders Department at Tufts, a graduate of and instructor at Harvard, the author of hundreds of psychiatric papers and dozens of books and educational programs; and he was a contributor to the authoritative, 2007 two-volume tome: Manic-Depressive Illness – Bipolar Disorders and Recurrent depression. Dr. Ghaeni is recognized around the world as an expert in the field. He is the author of the 2019 textbook Clinical Psychopharmacology – Principles and Practice. His website: https://www.psychiatryletter.net/ and podcast: https://anchor.fm/nassir-ghaemi/episodes/An-ignored-solution-to-suicide-e1inuh2 

The abstract for the Koukopoulos/Ghaemi paper (available without charge online) is presented here for an overview of its concepts:

In contemporary psychiatry, depression and mania are conceived as different entities. They may occur together, as in bipolar disorder, or they may occur separately, as in unipolar depression. This view is partly based on a narrow definition of mania and a rather broad definition of depression. Generally, depression is seen as more prominent, common, and problematic; while mania appears uncommon and treatment responsive. We suggest a reversal: mania viewed broadly, not as simply episodic euphoria plus hyperactivity, but a wide range of excitatory behaviors; and depression seen more narrowly. Further, using pharmacological and clinical evidence, and in contrast to previous theories of mania interpreted as a flight from depression, we propose the primacy of mania hypothesis (PM): depression is a consequence of the excitatory processes of mania. If correct, current treatment of depressive illness needs revision. Rather than directly lifting mood with antidepressants, the aim would be to suppress manic-like excitation, with depression being secondarily prevented. Potential objections to, and empirical tests of, the PM hypothesis are discussed. (bold added)

Despite this being published four years before the DSM-5, the definition of mania remained unaltered from the earlier DSM-III and IV. Even though the DSM-5 took a small step to broaden the highly restrictive DSM-IV definition of mixed states, it did not include the three symptoms most validated in the literature: irritability/anger, agitation, and distractibility (what would also be considered non-euphoric excitatory behaviors mentioned in the Koukopoulos/Ghaemi article). The committee deemed them “overlapping symptoms” from other “disorders;” and this neglect is one of the pitfalls of the DSM system.

Koukopoulos and Ghaemi discuss how the DSM from 1980 to the present intentionally defines depression broadly and mania narrowly. These definitions have shaped the education, clinical diagnosis, and treatment prescriptions of two generations of psychiatrists and mental health professionals, and yet it is contrary to the prior historical understanding of mania and depression dating to antiquity.  

Koukopoulos and Ghaemi illustrate that descriptions of mania from ancient Greece to the 1960’s offer a broad range of excitatory behaviors referred to as predominantly non-euphoric psychomotor excitation/agitation and have not been disproven by modern research.  Actually, research supports it. 


“For over 2000 years, mania was considered the main form of mental illness, with leading clinicians such as Pinel considering mania the most common form of mental illness…. Kraepelin, carrying on this tradition, had broad criteria for mania: his many categories of mixed states and his fundamental states (temperaments) were basically conditions of excitement.” 

Based on this history and recent research, the authors propose a provocative thesis: that mania can be seen as the core psychopathology of mood disorders, with depression its consequence,” a reversal of DSM thinking since the 1980 3rd edition. (bold added)

A shorthand definition of mixed states is helpful here. Mixed states can be seen as a few depressive symptoms that intrude upon predominant mania or a few manic symptoms that intrude upon predominant depression. How many is “a few” depends on how restrictive or expansive the research criteria are for a given study. This inexactness has been an area of controversy in recent years. The DSM mood disorders committee (mostly academics not conducting research) propose a restrictive definition while researchers like Koukopoulos and Ghaemi and others around the world, who are knowledgeable in the historical understanding, propose wider criteria.  

To broaden the restrictive DSM definition of mixed and manic states, the authors propose validated manic-equivalent symptoms described in the excerpt below:

“Mixed/agitated depressions, subthreshold for full DSM-IV mixed state criteria, can be characterized by motor agitation and/or psychic agitation manifested by lack of inhibition, intense inner tension, racing thoughts, unprovoked anger, talkativeness, early insomnia, mood lability, dramatic suffering and psychic pain.  In addition to the presence of excitatory symptoms, the course of mixed states differs from pure depressive episodes in that about 30% are followed by depression while hypomanic switch is rare. Further, unlike pure depression, antidepressants often worsen agitation and manic symptoms in depressive mixed states.” (bold added)

Euphoria, elation, and elevated mood are absent from their description, which the DSMs have incorrectly promoted as more common than they are in actual clinical practice. 

The symptoms in the excerpt above do not respond well to antidepressants which will:  1) do nothing, 2) increase those symptoms, i.e. mixity (most common outcome), or 3) occasionally produce full mania. 

These symptoms are more consistent with the historical descriptions of mania, but since 1980, they have been mistakenly labeled as “depression” because there is no “euphoria, elation or elevated mood.”  Historically, depression is a persistent slowing down of mind and body i.e., a lack of interest, motivation and mood reactivity whether the person is sad or not. 

Regarding antidepressants for Bipolar depression, Koukopoulos and Ghaemi state:

“Thus, we believe that an objective reading of the scientific literature throws the efficacy and safety of antidepressants in bipolar disorder into some doubt.”

Excerpt: More on Mixed states

“Also as noted above, mixed states are characteristic examples of the relevance of the PM hypothesis. If viewed broadly, so as to include both dysphoric mania and agitated depressive states with one or more other manic symptoms (such as flight of ideas, also called ‘‘depressive mixed states’’), the empirical literature suggests that about one half or more of acute manic episodes, and up to one half of major depressive episodes, are varieties of mixed states. This phenomenology would indicate that pure mania and pure depression are both less common than mixed states. The frequent presence of excitation as part and parcel of depressive presentations is consistent with the PM hypothesis and hard to explain based on the classic bipolar/ unipolar dichotomy.” (bold added)

According to Kraepelin6 and Ghaemi3, 60% of all mood presentations are mixed states (80% in children and adolescents), and only 20% are either full depression or mania. Therefore, 80% of mood states are represented as non-depressed and only 20% as depressed. This high percentage argues for a reconsideration of the DSM restrictive definitions of mixed and manic states. This conundrum was created in 1980 when the full disease entity of Manic-Depressive Illness was divided (based on limited research) into the broadly defined category of Major Depressive Disorder (MDD) and narrowly defined mania as if they were separate diseases. Historical understanding and research over the past quarter century has shown this to be a false reflection of actual presentations. 

The mixed symptoms, i.e.  manic equivalents, mentioned above of motor agitation and/or psychic agitation manifested by lack of inhibition, intense inner tension, racing thoughts, unprovoked anger, talkativeness, early insomnia, mood lability, dramatic suffering, and psychic pain are then called “Major Depressive Disorder” (MDD), instead of mania, and the treatment given is an antidepressant; thus the outcome is frequently more of the same. This is misdiagnosing mania as depression. The pervasive effects of the DSM’s overly loose definition of depression and overly compressed definition of mania is exemplified through clinical practice over the past 40 years since the DSM-III and can be seen as adverse consequences for patients who receive antidepressants instead of disease-modifying second-messenger modifiers like lithium, valproic acid, carbamazepine, or possibly lamotrigine. 



“According to the foregoing hypothesis, depression would follow, and be a consequence of, states of prolonged nervous arousal such as mania, hypomania, hypomanic equivalents, and anxiety. This hypothesis would support a parallelism between bipolar and unipolar depression. Continuous treatment with a mood stabilizer, as well as lifestyle changes designed to reduce stressors, may attenuate nervous arousal and, by doing so, prevent the genesis of future depression.” (bold added).

Koukopoulos and Ghaemi are not promoting a “new discovery” in their paper. They are promoting a re-understanding of the historical description of mania – one which is far broader than the confines of the DSM since 1980. To further illustrate the restrictive DSM mindset to which we are limited, the following quote from researcher and clinician J.D. Campbell in 1953,beautifully describes the rich variation in mixed and manic-depressive presentations in clinical practice: 

“There are more mixed reactions of this disease than is generally realized. It could truly be stated that, to some extent, all manic-depressive reactions are “mixed types”, in that symptomatology is anything but static…The mixed types of manic-depressive psychosis epitomize the entire cyclothymic process, in that it contains the symptoms characteristic of the various phases…Whether it is a sustained reaction or represents a phase of metamorphosis between the major forms, the mixed type emphasizes the underlying similarities between the depressive and the hypomanic, the fact that the manic and depressive reactions may be superimposed, and that the same individual possesses the same potentiality for either form…Manic-Depressive is a dynamic, constantly changing process which at times may manifest symptom of both phases simultaneously…It is in the mixed form that the observer graphically realized the homogeneity of the entire process.” (bold added)

The Dilemma of “mania” in Child and Adolescent Psychiatry 

Diagnosis and treatment is more problematic in child and adolescent psychiatry which prefers the strictest criteria for mania to prevent “overdiagnosis.”  Training programs in child and adolescent psychiatry are loath to consider irritability, anger outbursts, agitation, restlessness, disruptive behavior,  distractibility, and unstable, erratic moods as manic equivalents. Residents are not taught about the diagnostic hierarchy (see prior posts) where mixed and manic mood states are at the top of the hierarchy, psychotic states rank 2nd, anxiety states are 3rd (PTSD, OCD), and personality traits and ADHD are last.  In hospital charts I review, child and adolescent psychiatrists diagnose in a reverse order in spite of three important factors: (1) a positive family history for mixed and manic states, (2) voluminous literature documenting presence of these states in prepubertal kids and postpubertal teens, and (3) the fact that the FDA lowered the age for lithium from 12 to 7 in 2018 based on positive studies in these ages.

The DSM is replete with “off ramps” to detour doctors away from a diagnosis of mania: these are called ADHD, Oppositional Defiant Disorder, Conduct Disorder, Intermittent Explosive disorder, and the newest and controversial DMDD (Disruptive Mood Dysregulation Disorder). These “off ramps” will be used even when a parent has a bipolar diagnosis (even though there is 85% heritability for bipolar-I). The child will receive a list of stimulants, alpha 2 agonists (clonidine or guanfacine), and antidepressants, and sometimes simultaneously, but rarely a second messenger modifier (i.e mood stabilizer) like valproic acid, lithium (approved for 7-17  yrs.), or carbamazepine. The usual outcome is the child does not get better and the correct diagnosis is years away. Recently I saw an 11 yr old in a hospital with a combination of six of the above medications. Rarely does a patient need two or more “antibiotics” for one “infection;” and the same is true in psychiatry – using the correct hierarchical diagnosis would likely eliminate the “need” for multiple medications. 

An example in a teen’s chart I reviewed: Patient does report periods of time of higher energy with increased motivation and increased production of speech as well as racing thoughts.  It is unclear if these are manic in nature or not however.”

I would call this bending over backwards to avoid the diagnosis of mania. The correct medicine for this child would be lithium, which has been extensively studied in children and adolescents and found to be safe and effective. 

If not antidepressants – then what?

Most psychiatrists are at a loss of what to do when antidepressants are not recommended, which should amount to 60-80% of the time as mentioned above. The answer is low doses of second-messenger modifiers (aka ‘mood stabilizers’) like lithium, valproate acid, lamotrigine, and carbamazepine. These medicines have been on a 20-year decline 5 and are now the least prescribed medicines in psychiatry, with lithium given to only 17% of patients with mania. (In this study, ironically, any antidepressant was prescribed at 47.0% of the bipolar visits in 1997–2000 and 57.5% of the visits in 2013–2016.)   

 There are several  possible factors for this decline:

  1. The restrictive DSM definition of mania, and its expansive description of depression. 
  2. The inadequate education in training programs on lithium since the mid 1990’s when Depakote was introduced followed by lamotrigine (Lamictal) in the early 2000’s.
  3. Big Pharma promotion of 2nd generation dopamine blockers: (antipsychotics) like Zyprexa, Risperdal, and Abilify followed by others.

Many clinicians might prefer to avoid the blood tests involved with lithium, Depakote, and carbamazepine (Tegretol) since it would be easier to use lamotrigine or the dopamine blockers mentioned above. However, the convenience for the prescriber does not always help the patient get better. 

One patient with Bipolar illness reported her nurse practitioner said regarding lithium, “I’m not going to touch that stuff.”  The patient’s suffering is prolonged when the correct antibiotic” is avoided for the “infection.”  This exemplifies fear due to inadequate training, of the most effective medication in the history of psychiatry (with the exception of penicillin, a true miracle cure starting in the late 1940’s for early stages of neurosyphilis which caused severe manic, mixed, psychotic and depressive symptoms). Would that same prescriber be just as afraid to prescribe penicillin if neurosyphilis was diagnosed?  

To help clinicians diagnose the manic equivalents of mixed states, see the link below for the paper7 and rating scale. 

Anther resource: Hypomanic Checklist HCL-15 (see under resources)

However, it should be noted, talking to a spouse, close relative, friend or parent to elicit the non-depressive symptoms mentioned above is always preferred over questionnaires. 

  1. Michele Fornaro et.al. The argument of antidepressant drugs in the treatment of bipolar depression: mixed evidence or mixed states? Expert Opin Pharmacother. 2012 Oct;13(14):2037-51
  2. Koukopoulos A, Ghaemi SN. The primacy of mania: a reconsideration of mood disorders. Eur Psychiatry 2009; 24(2):125-34. 
  3. Ghaemi S.N.  Clinical Psychopharmacology – Principles and Practice, Oxford 2019.
  4. Goodwin F, Jamison K, Manic Depressive illness – Bipolar Disorders and recurrent Depression. vol. 1, 2nd edition 2007, Oxford Press. 
  5. Rhee TG et al. 20-Year Trends in the Pharmacologic Treatment of Bipolar Disorder by Psychiatrists in Outpatient Care Settings. Am J Psychiatry 2020 Aug 1;177(8):706-715
  6. Kraepelin E: Manic-Depressive Insanity and Paranoia. Edinburgh, Livingstone, 1921.
  7. Gabriele Sani, et.al. The Koukopoulos Mixed Depression Rating Scale (KMDRS): An International Mood Network (IMN) validation study of a new mixed mood rating scale. Journal of Affective Disorders Volume 232, May 2018, Pages 9-16

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