Sorting Out Comorbidities

Psychiatric TimesVol 38, Issue 11




The last column discussed how to improve precision in the diagnosis of mania and hypomania and how to identify likely prebipolar depressions that may evolve into a diagnosis of bipolar disorder (BD) following the onset of a subsequent manic or hypomanic episode. It is important to identify comorbid disorders that add to the symptoms of BD, so that these symptoms can be targeted appropriately. Some prescribers tend to target symptoms (eg, anxiety, insomnia, and irritability) with medications while leaving the underlying disorder(s) unrecognized and/or untreated.1

Taking Time for Diagnosis

Table. Common Challenging Comorbidities

Table. Common Challenging Comorbidities

When there is a comorbidity, one should first delineate the various DSM-5 diagnoses that are present (Table). The evaluation may require several meetings to reach the initial diagnostic impression, and it can take 90 minutes to evaluate a complex new patient, including reviewing the previous record and writing the assessment.2 Clinicians who are employed may not be allowed this much time, or if in private practice, they may elect to take less time because of financial considerations and pressures. Experienced clinicians may convince themselves that they can do an adequate assessment in less time and choose the correct medications for the correct diagnoses. However, a competent and comprehensive psychiatric evaluation requires time. Brief evaluations, followed by quick prescribing, are often experienced by patients as rushed and unsatisfying. Confidence in and respect for our profession is undermined by these practices.2 The first clinical encounter is an important moment that sets the stage for the ongoing therapeutic alliance.

After establish the diagnoses, determine (with the patient) those that may be contributing the most to the patient’s distress or dysfunction, and treat those first with what the evidence best supports. For example, active and severe substance use disorders may deserve priority management. Cannabis use disorder can exacerbate BD,3 and it may be important to persuade the patient to address this before introducing or modifying the medications prescribed for the BD and other disorders.

Treating Common Comorbidities

Posttraumatic stress disorder (PTSD) is a common comorbidity, especially in veterans. The irritability in PTSD—which can be triggered by events, interactions, or memories of their trauma—is easily mistaken for the irritable mood that is one of the mood types in the A criteria for bipolar mania (along with elevated or expansive mood) in the DSM-5. Valproate is often prescribed for irritable mood thought to be associated with mania, but the PTSD symptoms, including irritability, will likely not respond to it, as was demonstrated in 2 negative controlled studies.4,5 Determine whether the irritable mood occurs in discrete episodes of mania that last at least several days and are accompanied by the other manic symptoms in the mania criteria (noting that 4 other symptoms are needed if the mood is only irritable). If not, and the irritable mood is invariably occurring when triggered by events that produce reexperiencing and the fight-or-flight adrenalized immediate reactions to those triggers, then it is likely due to PTSD. For these patients, the treatment would likely be more effective with an antiadrenaline agent in the PTSD armamentarium such as prazosin or clonidine.

Attention-deficit/hyperactivity disorder (ADHD) is another comorbidity with BD. Most adults with ADHD have emotional dysregulation, which presents as chronic over-reactiveness to stresses.6 This, too, can be confused with the irritable mood of a manic episode. Stimulants have been found effective for this emotional dysregulation as well as for the focus, concentration, and hyperactivity associated with ADHD.6 It is important to make this diagnosis, using the DSM-5 criteria, and consider which symptoms could be attributed to ADHD and which occur mostly or to a greater extent during discreet manic episodes. Stimulants can, in fact, be used to treat ADHD in patients with comorbid BD.7

Sleep impairment is seen in comorbid diagnoses. In mania, there is decreased need for sleep, and the treatment of choice would be an antimanic agent rather than a hypnotic. However, often sleep impairment has other causes. There are medical causes, such as sleep apnea, restless leg syndrome (RLS), caffeinism, nocturia from prostate hypertrophy or diabetes, and pain syndromes, etc. Among psychiatric comorbidities, PTSD, which is associated with sleep disturbance, including difficulty initiating sleep and difficulty maintaining it due to nightmares, disturbed awakenings, and night terrors.

A thorough evaluation of insomnia is indicated to identify the leading cause(s), including asking about all examples of PTSD-related sleep disturbance. This is a much better approach than the shortcut of treating the insomnia symptom by proceeding through a list of hypnotics that might include antihistamines, benzodiazepines, zolpidem, gabapentin, melatonin, trazodone, mirtazapine, quetiapine, valproate, or some combination of these. Depending on the causes, the proper treatment might be continuous positive airway pressure, effective pain management, pramipexole for RLS, reduction of caffeine use, or prazosin for the nightmares and disturbed awakenings of PTSD.

Patients with BD are also prone to anxiety symptoms. It may be reasonable to use antianxiety agents like buspirone, benzodiazepines, or possibly gabapentin. However, there may be another disorder that is the primary cause of the anxiety. PTSD comes up again because the anxiety can be related to events, fears, triggers, and inability to avoid reminders of their trauma. Buspirone and benzodiazepines have not shown efficacy for that kind of anxiety, and antidepressants are probably best avoided in patients with BD. Prazosin, once again, might be the preferred treatment.8

Concluding Thoughts

Comorbidities in patients with BD are the rule rather than the exception. Good clinical practice requires us to spend the time to complete a comprehensive evaluation to tease out the various comorbidities and then to treat each one appropriately.

Dr Osser is an associate professor of psychiatry at Harvard Medical School and codirector of the US Department of Veterans Affairs’ National Bipolar Disorder Telehealth Program in Brockton, Massachusetts. The author reports no conflicts of interest concerning the subject matter of this article.


1. Baldessarini RJ. Chemotherapy in Psychiatry: Pharmacologic Basis of Treatments for Major Mental Illness. 3rd ed. Springer; 2013.

2. Osser DN. Psychopharmacology Algorithms: Clinical Guidance From the Psychopharmacology Algorithm Project at the Harvard South Shore Psychiatry Residency Program. Wolters Kluwer; 2021.

3. Mammen G, Rueda S, Roerecke M, et al. Association of cannabis with long-term clinical symptoms in anxiety and mood disorders: a systematic review of prospective studies. J Clin Psychiatry. 2018;79(4):17r11839.

4. Davis LL, Davidson JRT, Ward LC, et al. Divalproex in the treatment of posttraumatic stress disorder: a randomized, double-blind, placebo-controlled trial in a veteran population. J Clin Psychopharmacol. 2008;28(1):84-88.

5. Hamner MB, Faldowski RA, Robert S, et al. A preliminary controlled trial of divalproex in posttraumatic stress disorder. Ann Clin Psychiatry. 2009;21(2):89-94.

6. Faraone SV, Banaschewski T, Coghill D, et al. The World Federation of ADHD International Consensus Statement: 208 evidence-based conclusions about the disorder. Neurosci Biobehav Rev. 2021;128:789-818.

7. Viktorin A, Rydén E, Thase ME, et al. The risk of treatment-emergent mania with methylphenidate in bipolar disorder. Am J Psychiatry. 2017;174(4):341-348.

8. Osser DN. Comorbid PTSD: update on the role of prazosin. Psychiatric Times. 2021;38(4):21. ❒

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