What happened to Manic-Depressive Illness?
Is that the same as bipolar? 4.0

“Melancholia is the beginning and part of mania…The development of mania is really a worsening of the disease (melancholia) rather than a change into another disease."

-Aretaeus of Cappadocia ca. 100 AD

No, they are not the same. Kraepelin’s original unifying concept of recurrent depression plus what is now called ‘bipolar’ in the early 20th century, has not been disproven by any subsequent research.  Classic MDI referred to either recurrent depressive or manic episodes. For example:

  • A person could have 10 lifetime recurrent depressive episodes with no manic episodes and would be diagnosed with MDI.
  • Or a person could have multiple recurrent depressive episodes and a first manic episode in his or her 60’s (or just one manic episode in his entire life) and the diagnosis is still MDI. 
  • Rarely, a person could have recurrent manic episodes which would still be MDI. 
  • Another person could have recurrent manic and depressive episodes which under post DSM-III would be called “bipolar.


I do not like the term “bipolar,” and I would move to have it stricken from the record. It is overused professionally and in the general public without a full understanding of the Manic-Depressive Disease entity which also includes mood temperaments of cyclothymia, hyperthymia and dysthymia (to be discussed in a future blog). Mixed depressive and manic states i.e. depression with mild manic symptoms and mania with mild depressive symptoms are also included in MDI. 

What is not included in MDI is mild chronic depression formerly called “depressive neurosis” (mild depression with mild anxiety) which can be treated equally well with psychotherapy or SSRI meds, according to studies. 

However, since that is not likely to happen anytime in the near future, a history of its origin will show how it originated. 

What we call Bipolar since 1980 is actually a small subset of the larger disease entity of MDI. So why was the true disease entity of MDI broken into MDD and Bipolar in 1980?

The terms “bipolar” and “unipolar” were first coined by an east German psychiatrist Karl Leonhard in the late 1940’s because it was thought, due to an epidemiologic-genetic study at that time, there was a separation between the two, i.e., two separate illnesses. 

Leonhard and others made the basic distinction between them, one of “polarity” and not “recurrence,” as Kraepelin had originally described. This notion was furthered in family studies by Angst and Perris in the 1960’s which appeared to show, after less than a decade of follow up, a difference between families with alleged bipolar members and families with only depressive episodes. This was the basis of the unfortunate cleavage of Manic-Depressive Illness into separate MDD and Bipolar diagnoses in 1980. 

However, Jules Angst, a Swiss psychiatrist, continued his follow up studies on the same individuals in his original cohort from the 1960’s called the Zurich Cohort Study. He followed those patients for the next 40 years to the last survivor. This extended research provided data contrary to the hypotheses in the 1960’s, ultimately contradicting the original separation between two distinct diagnoses. There were “bipolar” relatives in the supposed unipolar cohorts and unipolar relatives in the supposed bipolar cohorts. 

Despite this significant discovery, science was ignored when the DSM-5 Mood disorders committee was not persuaded to reunite MDD and BP into the original disease entity of MDI. Therefore, the DSM’s separation between the two is based on a faulty and disproven hypothesis, and despite there being no subsequent research to support a separation of Bipolar from severe recurrent unipolar depression, the DSM has remained committed to that separation.  

Angst explains:

“Many genes may be involved in our vulnerability and capacity to manifest such changes of mood and activity. Molecular genetic data are compatible with dimensional concepts, suggesting more quantitative than qualitative differences between unipolar and bipolar disorders.”  Angst J, Do Many Patients with Depression Suffer from Bipolar Disorder? (Can J Psychiatry 2006:51:3–5)

“Research on the broad bipolar spectrum is dependent on the definition of hypomania. We recently proposed a new, softer syndromal definition with clinical validity. This broadens the diagnosis of bipolar II (BP-II) disorder at the expense of major depressive disorder (MDD). There is evidence for a third group of suspected BP-II manifesting major depression plus hypomanic symptoms. The two bipolar-II groups together are as prevalent as MDD. A new concept of minor bipolar disorder embracing dysthymia, minor and recurrent brief depression with hypomanic syndromes and symptoms is discussed.” (Angst J, Gamma A. A new bipolar spectrum concept: a brief review. Bipolar Disord 2002;4(Suppl 1): S11–S14.)

A series of Zurich Studies by Jules Angst et.al. have been published over the past 50 years. Nassir Ghaemi calls this the Framingham equivalent for psychiatry. 

Ghaemi explains further: 

The strongest argument is perhaps in Jules Angst’s own work, the Zurich cohort, which he started in 1959.  At the time of his famous 1966 paper, he had about half a decade of data. These early data were used for the radical rejection of Kraepelin’s MDI in 1980 with DSM-III.  In the 1980s and 1990s, Angst continued to follow his patients and he found that the clear distinctions began to go away. The course and genetics of the bipolar versus unipolar subjects began to merge. As a good scientist, he began to walk back his theory and argued for a broader bipolar spectrum, and a unipolar spectrum, both of which merged with each other – a perspective that begins to get close to Kraepelin’s MDI concept.  Angst proposed these changes for DSM-IV and DSM-5, and I led the International Society for Bipolar Disorders (ISBD) 2008 Diagnostic Guidelines Task Force where a consensus of world researchers supported Angst’s proposal. It was never even seriously considered by DSM-5.  Here’s the lesson: DSM-III made radical Leonhardian changes based on limited data but refused to make smaller changes decades later with much larger data, using literally the same database!”

(Tradition with Special Reference to Mania, Melancholia and Manic- Depressive Psychosis Collated 7 Nassir Ghaemi’s comments – May 7, 2020, inhn.org)

Angst, now in his 90’s could be considered a living “Godfather” of European psychiatry. 

In addition, multiple family and twin studies since the 1970’s clearly demonstrate a genetic relationship between Bipolar (heritability of 85%) and recurrent severe major depression (heritability of 34%).  (From Goodwin and Jamison).

“In short, the bipolar/unipolar distinction now calcified in DSM-III thru [sic] DSM-5, has not been supported by further research in mood disorders, and in fact that research could be used to support the original MDI perspective of one broad mood illness.” (Ghaemi, Clinical Pharmacology text 2019).

Incredibly, since 1980 when DSM-III severed Manic-Depressive Illness into a narrowly defined Bipolar “disorder” and a broadly defined Major Depressive “Disorder” (i.e., chronic and milder types of depressive presentations as well as severe recurrent melancholic depressions), there has been no genetic evidence produced that disproves the full disease entity of Manic-Depressive Illness as historically described.

In historian Edward Shorter’s 2015, “What Psychiatry left out of the DSM-5, he noted that 18th century physicians reported that “patients with serious depression left long enough will sooner or later develop an episode of mania or hypomania;” and “it did not occur these psychiatrists to carve out a special diagnosis based on polarity.”(bold added) These doctors were correctly focusing on long-term course, not polarity.

Shorter continues, “various scholars have remarked that among the first observers to see this alternation of mania and melancholia as parts of the same disease was the Spanish court physician Andres Piquer Arrufat, who described in 1759 the mentally ill king Fernando VI as having el afecto melancolico-maniaco… Piquer regarded the illness as a unitary condition (“son una misma enfermedad”). 

“Thus, for physicians there was nothing at all new about the concept of bipolar disorder, it was merely that there was no such thing as a unipolar disorder. Most major episodes of melancholia were “bipolar” and even if not, it made no difference. “  (Shorter)

In summary

Research over the past quarter century indicates clinicians should be questioning patients (and family members) for even the mildest manic symptoms, called hypomania, which patients rarely volunteer and which portend a poorer response to antidepressants. Also, practitioners have not been trained to understand or question for what are called Mixed Features or Mixed States (i.e. mild manic symptoms while depressed or mild depressive symptoms while manic) which have just entered the DSM-5 as of 2013. These mixed states respond poorly to antidepressants which may increase the mixed symptoms or increase suicidal thinking. This is true for children, adolescents, and adults. 

Mixed Features or States constitute 60% of Manic-Depressive Illness with only 20% of patients having pure depression and 20% having pure mania. 

So 80% of patients have mixed or manic states which do not respond well to antidepressants and about 20% of patients will have a good response to antidepressants. 

Clinically, Depakote appears to work better for mixed states than lithium, but lithium is better for prevention of manic and depressive episodes and is the only medication which has been proven to prevent suicides and protect the brain. 

Since 1980, two generations of psychiatrists have been trained to either not question for, or to discount mild manic symptoms. I reviewed a chart recently where a psychiatrist wrote: 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.” Yes, these are clearly manic symptoms, and the patient should be considered for lithium, Depakote, Lamictal/lamotrigine or Tegretol/carbamazepine (these are referred to as mood stabilizers) rather than antidepressants no matter how much the patient talks about feeling depressed. 

This is a major area of controversy in psychiatry. Some experts say not to  prescribe antidepressants unless the patient is taking one of the mood stabilizers mentioned above, and other experts say the addition of antidepressants will decrease the effectiveness of a mood stabilizer and should not be used at all. 

Recently Latuda/lurasidone and Caplyta/lumateperone (both dopamine blockers with serotonin influence) have been FDA approved for bipolar depression which would be preferred over antidepressants. However old habits die hard, and the past two generations of psychiatrists were raised on a steady diet of big-pharma promoted antidepressants. 

The broadly defined MDD in the 1980 DSM-III turned out to be a windfall for the pharmaceutical industry because for virtually any patient saying he or she felt depressed in some way (regardless of mild manic or mixed states) there was an immediate remedy. Coincidentally, in the late 1980’s the first SSRI meds were introduced. Prozac followed quickly by Zoloft which had fewer dangerous side effects compared to the Tricyclic and Monoamine oxidase (MAOI) antidepressants. 

Footnote:  Since the 1990’s the term Bipolar Spectrum (not in the DSM) has been used frequently in the psychiatric literature, sometimes  as a substitute for Manic-Depressive illness and sometimes as a way to broaden the narrow DSM concept of Bipolar disorder.  Hagop Akiskal published several papers on his conceptualization of Bipolar I-V, to be discussed in a future blog. 

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