It has been documented since Kraepelin’s classification in the early 20th century to the present, that up to 60% of all mood illness presentations are really “mixed states” or “mixed episodes” i.e., not pure depression with psychomotor slowing and not pure mania with psychomotor activation/excitation.

In other words, it is the norm for some mild, manic symptoms to intrude in a depressive episode and conversely for some depressive symptoms to intrude in a mild manic episode. Pure depressive or manic states are the exception.

Based primarily on the overly broad DSM definition of “MDD,” which includes the mildest to the most severe depressions, a standard of care has arisen where practitioners screen all patients for “depression” using the PHQ-9 or equivalent, which virtually preordains that the diagnosis will be depression followed by an  automatic prescription of an antidepressant.

But this screening is like only looking at one side of a coin or never looking for the dark side of the moon, and assuming it’s not there, leaving open the question: is this a pure, unipolar depression, a bipolar depression, or a mixed depression?

The vast majority of patients who may have a bipolar illness, diagnosed or not, will usually present in a depressed state. It is the duty of the clinician to attempt to make this all-important distinction so the right treatment can be given. I explain this to patients as getting the right diagnosis so we can choose the right “antibiotic,” i.e., antidepressants do not help in mixed or manic states, only in a pure depression.  Patients understand this analogy.

Using the aforementioned Diagnostic Hierarchy and Diagnostic Validators elaborated in prior blogs are the first step. 

Here are some clinical points from Manic Depressive Illness – Bipolar Disorders and Recurrent Depression, Frederic K. Goodwin and Kay Jamison 2007.

• The patient’s self-report is not sufficient for a dependable denial of past hypomanic or manic episodes, due to the problem of lack of insight, considering any mood that is not depressed as “normal.”
• Also, patients are often in such psychic pain during a depressive episode that they can be unmotivated to search their memory carefully for times when they may have felt better (albeit pathologically).
• It is strongly recommended by many experts that before a patient be given a diagnosis of “MDD,” i.e., pure unipolar depression, a close family member or spouse needs to be contacted to elicit subsyndromal or syndromal hypomanic or manic and/or mixed symptoms, if any, before prescribing antidepressants.

• False unipolar depression, sometimes called pseudo-unipolar depression characterized by non-euphoric psychomotor agitation, irritability and distractibility, i.e., mixed states, occurs in at least 50% of supposed MDD (higher on inpatient) since it is well known that patients rarely volunteer these symptoms but will call themselves “depressed” because they feel unhappy.  Relatives, however, do report these symptoms as well as subsyndromal hypomanic symptoms.

From: Mood Disorders: A Spectrum Analysis – Neuroscience Educational Institute presentation 2016. Stephen Stahl MD

• In the spectrum concept if you have a touch of mania while depressed you will eventually become bipolar. 

• 1/3rd of unipolar depressions eventually diagnosed as bipolar. 

• As many as 60% of patients diagnosed as Bipolar II are initially diagnosed as unipolar.

• The presence of even some subthreshold (hypo)mania is strongly associated with conversion to bipolar. 

• Each hypomanic symptom increases the bipolar risk by 30%.

From: Guidelines for the recognition and management of mixed depression. Stahl S. et.al. CNS Spectrums (2017), 22, 203–219. © Cambridge University Press 2017.

• Not all patients with depression (as part of bipolar disorder or major depressive disorder) should be prescribed an antidepressant. 
• All patients who receive antidepressants for an MDE should be monitored for signs of abnormal behavioral activation or psychomotor acceleration.
• The use of antidepressants in MDE patients with mixed features may not alleviate depressive symptoms and may pose a potential hazard for exacerbating subthreshold mania symptoms that accompany depression. 
•  For an individual presenting with a depressive episode with mixed features, in addition to antidepressant medication, alternative psychotropic agents (e.g., lithium, anticonvulsant mood stabilizers, atypical antipsychotics) with demonstrated efficacy in treating depressive symptoms as part of MDE may be considered. 

•  You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask! 

• Ask every patient. Every time.

From: Neurosciences Educational Institute -presentations 2016-2019

Figure from: Guidelines for the recognition and management of mixed depression. Stahl S. et.al. CNS Spectrums (2017), 22, 203–219. © Cambridge University Press 2017.

There are several screening questionnaires which, in my opinion, need to be given before the PHQ-9. I will review others in the future but these two are the most well known and validated. 

Mood Disorder Questionnaire – developed by Hirschfeld and colleagues, can serve as a screening tool and should be given to depressed patients to evaluate the likelihood of a prior manic or hypomanic episode. 

• The MDQ consists of 13 yes/no questions derived from the DSM-IV criteria for bipolarity and clinical experience. If the patient checks off seven or more “yes” answers, several of these “yes” symptoms co-occurred, and this resulted in at least moderate psychosocial impairment, then there is a good likelihood of a past manic or hypomanic episode. 

• The MDQ was validated in a study of 198 patients being treated in outpatient psychiatry clinics and demonstrated that patients with a screening score of 7 or more “yes” answers achieved a sensitivity of 0.73 and a specificity of 0.90 for identifying patients with bipolar spectrum disorder. 

• Thus, although the MDQ is not diagnostic for bipolarity, it can help guide the evaluating clinician as to how to direct the clinical interview.

Hirschfeld R, Williams J, Spitzer R, et al. Development and Validation of Screening Instrument for Bipolar Spectrum Disorder: The Mood Disorder Questionnaire. Am J Psychiatry. 2000; 157:1873-1875.

For comparison: A positive RF result was strongly associated with rheumatoid arthritis or another rheumatic disease. For rheumatoid arthritis, sensitivity=0.28 and specificity=0.87, while for any rheumatic disease, sensitivity=0.29 and specificity=0.88.

Hypomania Checklist (HCL–32) Patient self-report that screens for lifetime (hypo)manic symptoms—this does not assess mixed episodes, and has not been suggested to do so.

Hypomania checklist (HCL-15) – The sensitivity of 15-HCL in detection of BP-II was 0.78 and 0.46 for BP-I; the specificity was 0.9 and 0.69, respectively. The specificity of HCL-15 for BP versus MDD was as high as 0.93. (He H. The use of 15-point hypomanic checklist in differentiating bipolar I and bipolar II disorder from major depressive disorder. Gen Hosp Psychiatry. 2014 May-Jun;36(3):347-51)

Treatment Implications

Lithium and penicillin are considered to be the two most effective medicines in psychiatric history. (Lithium and ECT are the most successful treatments.)  

Penicillin was a miracle cure for early stages of neurosyphilis, and it helped hundreds of patients who had been hospitalized for all types of mania, depression, and psychosis to leave psych wards starting in the late 1940’s. 

Lithium was approved in the U.S. in 1970 (the last developed country to approve it), and it has been called the DMARD of psychiatry by Nassir Ghaemi because it can change the course of classically defined Manic-Depressive Illness and prevent future episodes. No antidepressant can change the course of any psychiatric “disorder;” they only mollify the symptoms, but not the course.  

Unfortunately, lithium has been deemphasized in psychiatric training programs since the approval of two medications marketed as treatments for mania:  valproic acid (Depakote) was approved for use in 1995 (extended release approved in 2006) for “acute mania (divalproex) and mixed episodes,” and lamotrigine was approved in 2003 by the FDA for “maintenance and treatment of Bipolar I to delay the time and occurrence of new mood episodes.” 

“And now for the rest of the story” as a well- known radio commentator used to say in a bygone era. 

According to Nassir Ghaemi in his 2019 Clinical Psychopharmacology text:

• Lithium is highly effective in depression prophylaxis in bipolar and unipolar illness. 
• Lamotrigine is not proven to be more effective than lithium in depressive prophylaxis in bipolar illness using unbiased research designs, i.e., “enriched studies.”
• Lithium robustly prevents depressive and manic episodes whereas lamotrigine is better at preventing depression than mania.
• Lamotrigine is not effective in treating either acute episodes of mania or depression, and is not FDA approved for this, only future episodes. 

(from Clinical Psychopharmacology Principles and Practice- 2019)

Antidepressants?

• Antidepressants are proven ineffective in treating the acute depressive episodes in bipolar illness.
• Antidepressants are proven ineffective in treating and preventing future episodes of BP illness.
• Antidepressants are proven to cause acute mania in bipolar illness.
• Antidepressants are proven to cause more and more mood episodes over time in about one quarter of patients with BP- illness.
• Antidepressants are ineffective at best, and harmful at worst, in BP illness.

Roger McIntyre 2016 presentation with Neuroscience Educational institute handout; We can do better: Improving the Recognition and treatment of Bipolar Depression.  

• Antidepressants do nothing –most common outcome.

1.  2nd most common outcome: Antidepressants may cause destabilization or instability manifesting at dysphoria, anxiety, irritability, volatility, and impulsivity that does not fit neatly into hypomania. 
2. Antidepressants most often induce “mixity” rather than hypomania. 

Recommendations from the NIMH-funded 2009 Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD):

• Antidepressants were not effective in acute bipolar depression when combined with standard mood stabilizers (lithium, Depakote-valproate, carbamazepine-Tegretol).

• Antidepressants should be avoided in most, if not all, cases when treating acute depression in patients with mixed or bipolar disorder.
• Rather, one should choose from among 6 medications with a reasonable evidence-base for effectiveness and safety in treating or at least preventing bipolar depressions, namely: 
• lithium, quetiapine, lamotrigine, lurasidone, and cariprazine, lumateperone (approved in 2022)—or a combination of these.

Weight gain most to least: valproate>lithium and carbamazepine or lamotrigine none. 

FYI for practitioners:

• Lab reference ranges for lithium were created for manic episodes not depression.
• After the manic episode has subsided, usually after a week or two, the dosage of lithium can be lowered so the blood level can be at the lower end or slightly below the reference range. 
• Mania usually requires 900-1200 per day until the mania subsides, then the dose can be lowered to 450-900 mg per day for maintenance.  
• Lithium is proven effective for prevention not only of future manic episodes but future depressive episodes as well.
• Lithium is now recommended to be taken only once a day with extended release since that has been shown to be safer for the kidneys than 2-3 times a day with immediate release (Eskalith CR, Lithobid slow-release tablets).
• No depressed person should be pushed into the lab reference range or he or she will frequently develop side effects and then not want to take it.  
• Lithium can be taken for decades with a risk of chronic renal insufficiency at 1% after 20 years. Eskalith CR, Lithobid slow-release tablets.
  
  

(More on lithium in a separate post)