“Impulsivity” and “compulsivity” are 2 constructs that typify a range of disorder presentation. Impulsivity encompasses a predisposition toward poorly conceived actions, taking undue risks, and a lack of consideration when making decisions. Compulsivity is thought of as an inappropriate and maladaptive persistence of repetitive behavior, undertaken according to rigid rules and/or as a means of avoiding perceived negative consequences. However, when we examine co-occurrence of mental health disorders, we often see impulsive and compulsive disorders within the same individuals.

For example, rates of substance use disorders (typically considered impulsive behaviors) are considerably higher in people with body dysmorphic disorder (ie, a prototypical compulsive disorder) than in the population at large (49% compared with 29%). Conversely, rates of OCD (a compulsive disorder) are elevated relative to the general population in people with bipolar disorder (a disorder characterized often by impulsivity) (11% compared with 2%).

Impulsive and compulsive problems are often examined separately as disparate constructs, but the co-occurrence and fluidity by which the two constructs may transition from one to the other suggest that some shared variance, and common brain mechanisms, may contribute to both. Thus, while impulsive and compulsive behaviors may exist in isolation, it also may not be uncommon for an individual to struggle with both drives simultaneously.

Features of impulsive and compulsive behavior when they co-occur may reflect a lack of control over thoughts and behavior and may suggest a trans-diagnostic ‘disinhibition’ phenotype.If true neurobiologically, then we need to think about treatment approaches to these co-occurring but perhaps atypically pared features and the treatments may need to target some shared underlying construct such as disinhibition.

is professor, Department of Psychiatry & Behavioral Neuroscience, University of Chicago. He spoke at PsychCongress in a presentation titled "When Trouble Strikes Twice: Addressing the Complex Needs of Patients with Both OCD and Mood Disorders."

1. Grant JE. Clinical practice: Obsessive-compulsive disorder. 

. 2014;371(7):646-653. doi:10.1056/NEJMcp1402176

Videos

Psych Congress

Impulsive and compulsive behaviors intersect and commonly occur within the same individuals.

Addressing the Impulsive Side of Compulsivity (And Vice Versa)

The COVID-19 pandemic has hit particularly hard on older individuals, who are more susceptible to serious illness as a result of underlying comorbid conditions. We see a similar phenomenon in many natural disasters, in which age is often a liability in terms of physical injury and death. Not surprising, we end up defining aging in terms of decline, disease and death, and viewing older individuals solely as potential victims. This attitude limits the way in which we can communicate with and learn from the elders in our lives—and it leads us, in turn, to denigrate our own aging selves.

Here is a counterpoint to this approach: aging brings key strengths that enable us to make better decisions, cope better, and even thrive during adversity: 

1. Wisdom
2. Resilience
3. Purpose
4. Creativity

Wisdom is one key strength, based upon not only all of the skills, experiences and knowledge that we accumulate with age, but also on ways in which our brains and minds draw upon and integrate different parts and perspectives better.

Research tells us that aging minds are more positive, practical and less emotionally reactive and impulsive. This wisdom make us more psychologically resilient as we age, enabling us to cope better with adversity. We can couple these strengths with a sense of purpose that often grows and deepens with age, conferring all sorts of benefits including improved wellness, fewer cardiovascular events, and even longer lives.

Another emergent strength is creativity, enabling us to express ourselves through art, relationships, volunteer work and other endeavors that can transcend the many physical and cognitive changes that may otherwise bog us down with age. Put together, the clear lesson here is to learn from and be inspired and guided by both aging and the elders around us. We need to celebrate the strengths that only aging can confer.

is a geriatric psychiatrist and senior vice president for Behavioral Health and the chief medical officer for MIND Institute at Miami Jewish Health. His discussed these issues during his “The Top Dos and Don’ts in the Psychopharmacologic Treatment of Geriatric Patients: Focus on Dementia and Late-Life Depression and Anxiety” presentation at Virtual Psych Congress 2020.

We need to celebrate the strengths that only aging can confer.

4 Components of Positive Aging

Bipolar disorder is a serious illness resulting in significant psychosocial morbidity and excess mortality. Through the years a number of research reports, reviews, and commentaries have suggested that bipolar disorder is underrecognized, and that many patients, particularly those with 

 Even for those patients in whom bipolar disorder is eventually diagnosed, the lag between initial treatment seeking and the correct diagnosis is often more than 10 years.

 The treatment and clinical implications of the failure to recognize bipolar disorder in depressed patients include the underprescription of mood stabilizing medications, an increased risk of rapid cycling, and increased costs of care.

 Recommendations for improving the detection of bipolar disorder include careful clinical evaluations inquiring about a history of mania and hypomania and the use of screening questionnaires.

Although the research is less robust, some studies have also found that bipolar disorder is sometimes overdiagnosed. 

 evaluated 21 patients with a substance use disorder who were admitted for residential treatment and had been previously diagnosed with bipolar disorder. Only 9 (42.9%) were diagnosed with bipolar disorder when administered a semi-structured interview. The other 12 patients were diagnosed with a substance-induced mood disorder. 

 evaluated 85 patients admitted to an inpatient dual diagnosis unit specializing in the treatment of mood and substance use disorders who had been diagnosed with bipolar disorder by their outpatient psychiatrist. Similar to the results of Stewart and El-Mallakh, only a minority of the patients (32.9%) had the diagnosis of bipolar disorder confirmed.

As part of the Rhode Island Methods to Improve Diagnostic Assessment and Services (MIDAS) project, our clinical-research group conducted the largest study of bipolar disorder underdiagnosis and overdiagnosis.

 We used the Structured Clinical Interview for DSM-IV (SCID) to interview 700 psychiatric outpatients presenting for treatment. Before the interview, the patients completed a self-administered questionnaire which asked them whether they had been previously diagnosed by a health care professional with bipolar or manic-depressive disorder. Family history information was obtained from the patients regarding their first-degree relatives. Slightly more than 20% of the sample reported that they had been previously diagnosed as having bipolar disorder (n = 145, 20.7%), significantly higher than the 12.9% rate based on the SCID. More than half (56.6%, n = 82) of 145 patients who reported that they had a previous diagnosis of bipolar disorder did not have a diagnosis of bipolar disorder based on the SCID. Bipolar disorder was also underdiagnosed in some patients, but three times as many patients had been overdiagnosed as had been underdiagnosed (82 

Patients with SCID diagnosed bipolar disorder had a significantly higher morbid risk of bipolar disorder in their first-degree relatives than patients who self-reported a previous diagnosis of bipolar disorder that was not confirmed by the SCID. A family history of bipolar disorder was similar in patients who self-reported a previous diagnosis of bipolar disorder that was not confirmed by the SCID and patients who were negative for bipolar disorder by self-report and the SCID. Thus, the results of the study suggested that bipolar disorder was sometimes underdiagnosed, more often overdiagnosed, and the family history analyses supported the validity of the diagnostic procedures.

In a follow-up to this initial study we examined whether there was a particular diagnostic profile associated with bipolar disorder overdiagnosis.

 We compared the diagnostic characteristics of 2 groups of patients who were not diagnosed with bipolar disorder based on the SCID interview—those who reported previously being diagnosed with bipolar disorder (n = 82) and those had not been so diagnosed in the past (n = 528). We conducted a logistic regression analysis to examine which diagnoses were independently associated with bipolar disorder overdiagnosis and found that borderline personality disorder, posttraumatic stress disorder and any impulse control disorder were independently associated with bipolar disorder overdiagnosis. Nearly 40% (20/52) of the patients diagnosed with DSM-IV borderline personality disorder had been overdiagnosed with bipolar disorder.

Thus, under- and overdiagnosis of bipolar disorder is possible. Recommendations for addressing the underdiagnosis problem include careful clinical evaluations inquiring about a history of mania and hypomania (which might include an interview with informants) and the use of screening questionnaires.

 Several scales have been developed to screen for bipolar disorder.

Administration of a screening scale is the first stage of a 2-stage diagnostic process. The more expensive and extensive second stage is only conducted when the patient screens positive. Consequently, it is important for a screening scale to have high sensitivity. Clinicians who rely on the screening scale as the first stage of a 2-stage diagnostic assessment, with the second stage being the more in-depth diagnostic interview, will miss the diagnosis in patients who are false negatives on the screening instrument.

 of studies of the Mood Disorders Questionnaire (MDQ), the most frequently studied screening scale for bipolar disorder, found that the MDQ’s sensitivity was 62% based on the recommended cutoff of 7.

 Thus, more than one-third of true cases of bipolar disorder would be missed if the MDQ was relied upon as the first stage of a 2-stage diagnostic process. In general psychiatric outpatient practices, the positive predictive value of the MDQ (ie, the likelihood of a patient who screens positive having bipolar disorder) is less than 50%.

Putting aside the performance statistics of bipolar disorder screening scales, the use of these scales can be questioned at a conceptual level. The reason for suggesting the use of these scales is that bipolar disorder is underdiagnosed. But the advocates for the use of screening questionnaires do not indicate how and why a paper-and-pencil questionnaire is expected to help improve diagnostic recognition? Are mental health clinicians often failing to inquire about a history of mania/hypomania in depressed patients, and will only do so when a screening scale is first completed? Do mental health clinicians not know what questions to ask to assess prior manic/hypomanic episodes and therefore these scales are needed because the scales ask the right questions that clinicians do not ask? Do mental health clinicians know what questions to ask, but ignore or discount positive responses from patients and this is the cause of bipolar disorder underdiagnosis?

That is, do the advocates of bipolar disorder screening scales believe that self-report screening questionnaires will improve bipolar disorder recognition because the results of these tests are less easily ignored than the responses of a patient to a clinical interview? Researchers of the performance of bipolar disorder screening scales have not addressed these questions in the Discussion sections of their papers.

I would argue that bipolar disorder screening questionnaires are superfluous. Because bipolar disorder screening scales have modest sensitivity, a clinical interview is necessary to reduce false negatives. Because bipolar disorder screening scales have modest positive predictive value, a clinical interview is necessary to reduce false positives. Thus, a clinical evaluation is always needed regardless of the results of the screening test. Consequently, it is not clear how a screening scale for bipolar disorder would be helpful in a psychiatric setting. The advocates of bipolar disorder screening, who suggest that such scales be routinely used in clinical practice, should indicate how these measures should interface with a clinician’s evaluation. By my reckoning a clinical evaluation is needed regardless of the results of the screening scale; thus, it is unclear what niche these measures should occupy.

is Professor of Psychiatry and Human Behavior, Brown University; Director of Outpatient Psychiatry and Partial Hospital Program, Rhode Island Hospital, Brown Medical School. He spoke at Psych Congress in a presentation titled “Does My Patient Have Bipolar Disorder? A Review of Diagnostic Concerns, Conundrums, and Confusion and What to Do About It.” The author reports no conflicts of interest concerning the subject matter of this article.

1. Bowden CL. Strategies to reduce misdiagnosis of bipolar depression. 

2. Katzow JJ, Hsu DJ, Ghaemi SN. The bipolar spectrum: a clinical perspective. 

3. Manning JS, Haykal RF, Connor PD, Akiskal HS. 

On the nature of depressive and anxious states in a family practice setting: the high prevalence of bipolar II and related disorders in a cohort followed longitudinally

1997;38:102-8. doi: 10.1016/s0010-440x(97)90089-4.

4. Ghaemi SN, Boiman EE, Goodwin FK. Diagnosing bipolar disorder and the effect of antidepressants: a naturalistic study. 

5. Ghaemi SN, Ko JY, Goodwin FK. "Cade's disease" and beyond: misdiagnosis, antidepressant use, and a proposed definition for bipolar spectrum disorder. 

6. Hirschfeld RM. Bipolar spectrum disorder: improving its recognition and diagnosis. 

7. Hirschfeld RM, Vornik LA. Recognition and diagnosis of bipolar disorder. 

8. Yatham LN. Diagnosis and management of patients with bipolar II disorder. 

9. Hantouche EG, Akiskal HS, Lancrenon S, et al. Systematic clinical methodology for validating bipolar-II disorder: data in mid-stream from a French national multi-site study (EPIDEP). 

10. Perugi G, Akiskal HS, Lattanzi L, et al. The high prevalence of "soft" bipolar (II) features in atypical depression. 

11. Hirschfeld RM, Lewis L, Vornik LA. Perceptions and impact of bipolar disorder: how far have we really come? Results of the National Depressive and Manic-Depressive Association 2000 survey of individuals with bipolar disorder. 

12. Lish J, Dime-Meenan S, Whybrow P, et al.The National Depressive and Manic-depression Association (DMDA) survey of bipolar members. 

13. Birnbaum HG, Shi L, Dial E, Oster EF, Greenberg PE, Mallett DA. Economic consequences of not recognizing bipolar disorder patients: a cross-sectional descriptive analysis. 

14. Shi L, Thiebaud P, McCombs JS. The impact of unrecognized bipolar disorders for patients treated for depression with antidepressants in the fee-for-services California Medicaid (Medi-Cal) program. 

15. Matza LS, Rajagopalan KS, Thompson CL, de Lissovoy G. Misdiagnosed patients with bipolar disorder: comorbidities, treatment patterns, and direct treatment costs. 

16. Isometsa E, Suominen K, Mantere O, et al. The Mood Disorder Questionniare improves recognition of bipolar disorder in psychiatric care. 

Is bipolar disorder overdiagnosed among patients with substance abuse?

18. Goldberg J, Garno J, Callahan A, et al. 

Overdiagnosis of bipolar disorder among substance use disorder inpatients with mood instability

19. Zimmerman M, Ruggero CJ, Chelminski I, Young D. Is bipolar disorder overdiagnosed? 

20. Zimmerman M, Ruggero CJ, Chelminski I, Young D. Psychiatric diagnoses in patients previoulsy overdiagnosed with bipolar disorder. 

21. Angst J, Adolfsson R, Benazzi F, et al. The HCL-32: towards a self-assessment tool for hypomanic symptoms in outpatients. 

22. Hirschfeld R, Williams J, Spitzer R, et al. Development and validation of a screening instrument for bipolar spectrum disorder: The Mood Disorder Questionnaire. 

23. Parker G, Fletcher K, Barrett M, et al. Screening for bipolar disorder: the utility and comparative properties of the MSS and MDQ measures. 

24. Ghaemi SN, Miller CJ, Berv DA, Klugman J, Rosenquist KJ, Pies RW. Sensitivity and specificity of a new bipolar spectrum diagnostic scale. 

25. Wang HR, Woo YS, Ahn HS, Ahn IM, Kim HJ, Bahk WM. 

The validity of the Mood Disorder Questionnaire for screening bipolar disorder: A Meta-Analysis

26. Zimmerman M, Galione J. Screening for bipolar disorder with the Mood Disorders Questionnaire: A review. 

Articles

Overdiagnosis of bipolar disorder is as important to guard against as its underdiagnosis. The use of bipolar disorder screening tools is questioned.

Diagnosing Bipolar Disorder in Clinical Practice: Underdiagnosis, Overdiagnosis, and Screening 

Last month, I was contacted by a psychiatrist seeking to consult my expertise in transgender care for a clinical dilemma. A patient of hers needed a second letter for surgery from a psychiatrist in order for the surgery to be covered by insurance. The patient’s therapist had already written a letter supporting surgery. The psychiatrist was aware that the World Professional Association for Transgender Health Standards of Care 7 (

) criteria for surgery was that mental illness was “well-controlled.”

 The patient had missed appointments with the psychiatrist for treatment of a mood disorder with substance use. However, the psychiatrist felt the patient would benefit from surgery. Could she write the letter?

As a co-author of WPATH SOC 7, I had heard variations on this question many times. And as chapter lead of the mental health chapter in the upcoming WPATH SOC 8, I have been working to try to provide more clear guidance to psychiatrists and other mental health professionals on the care of transgender people who also have mental illness and substance use disorders.

Since 1979, WPATH has periodically revised its Standards of Care, which choreograph the multidisciplinary care of transgender (or trans) people who are transitioning.

 Mental health professionals or primary care providers can assess patients for starting hormones. One or 2 evaluations from mental health professionals are recommended before surgery. Criteria for surgery include capacity for informed consent, persistent gender dysphoria, and that mental illness, if present, is “well-controlled.” There is a recommendation that patients live in the gender role in which they intend to live, and be on a stable hormone regimen, if indicated, for a year before genital reconstruction surgery.

From 1981 to 2014, the US Department of Health and Human Services banned reimbursement under Medicare for trans care. Coverage was excluded under Medicaid programs and most private insurance as well. The lack of insurance coverage meant that many trans people lacked access to care, and little trans care was provided by most health systems. Research was not funded in the United States.

 Physicians did not receive much training in trans care in medical schools, because academic health centers provided little care. All of this has changed dramatically in the last decade, and with increasing patient visits, training health providers in care for trans people has new urgency.

 Many states now require state-regulated private insurance and Medicaid coverage for transgender care, including surgery. Medicare has removed its ban on trans care coverage, though approval of surgical procedures are on a case-by-case basis. The Obama administration attempted to remove trans health exclusions in all states under Rule 1557 of the Affordable Care Act, though these efforts have been hampered by the current administration and a federal judge’s ruling. Removal of remaining trans health insurance exclusions awaits future court decisions or perhaps the next administration. But there has been a national sea change in insurance coverage since 2013.

Because of these funding restrictions, there was little research on trans-care and mental health in the United States until the past decade, but there has been data from European studies on mental health in trans people. Swedish lifetime longitudinal data showed that trans people there who had transitioned with social transition, hormones, and surgery still had increased mental health morbidity and mortality compared to the general population.

 However, the regret rate for transition in Sweden from 1960-2010 was very 

 A recent analysis of the Swedish data on initial publication showed a 

 in mental health utilization in those who had surgery versus those who had not

; however, the paper’s statistical analysis has been 

 of 72 studies from 1991 to 2017, that transition reduces gender dysphoria, improves quality of life, and that regret rates for transition are low.

The World Professional Association for Transgender Health is now working on the Standards of Care Version 8, due to be released in 2021. WPATH SOC 8 is a far larger effort than previous Standards of Care, with many experts in transgender health from around the world participating. Of note, a far larger share of the experts are health professionals who are themselves trans.

SOC 8 includes a separate chapter in which a majority of the authors are psychiatrists, working on guidelines for patients who are trans who also have mental illness and substance use disorders. This mental health chapter, for which I am chapter lead, agreed on approximately 20 statements for which we could reach consensus on principles of care for this population. Of these, the editors chose 10 statements that are considered action statements, which guide clinician actions. These statements went to a Delphi process to reach agreement from all of the experts from all of the chapters of SOC 8. The remainder of our statements, which weren’t action statements but rather statements of good practice, may still make it into the descriptive text of the chapter.

One major shift has been away from the requirement that mental illness and substance use disorders be “well-controlled” for the patient to proceed to surgery. Instead first, the mental illness, as is the case with other surgeries, must not impair the ability to give informed consent. Second, taking the mental illness or substance use disorder into account, the benefits of proceeding to surgery must outweigh the risks. A short delay to stabilize a patient psychiatrically might be worthwhile, but the risk of delay, with exacerbation of gender dysphoria, also needs to be considered. Psychosocial and practical care can support proceeding to surgery.

In the case where the psychiatrist asked me about a patient, a moderate mood disorder with substance use in many cases would not impair ability to give informed consent. If mental illness and substance use were preventing the patient from keeping appointments for needed perioperative care, a plan for support from family or friends to assist the patient in keeping appointments might allow surgery to proceed. Other agreed upon statements include keeping a patient on longstanding hormones (unless contraindicated) when admitted to inpatient psychiatry and taking steps in inpatient and residential settings to respect patients’ gender identity.

Each of the other chapters, approximately 20 in total, also have gone through a process like that described for the mental health chapter. In addition, for the medical and surgical chapters, consultants from Johns Hopkins University conducted literature reviews and rated the evidence from clinical trials of recommended interventions.

One of the new chapters in SOC 8 will be on care of people with non-binary identities. This continues a shift in SOC, which began with the 7th Version, away from binary preconceptions of identity and of transition. An increasing number of people identify as neither male nor female, but may still experience gender dysphoria, and may still need transition care.

Much progress has been made in the past several years in caring for trans patients. With this expansion of care and recent return of care of transgender patients (including surgery) to academic medical centers, there is the promise of more research and knowledge into providing better care. Psychiatrists play an important role, especially in the care of trans people with mental illness and SUDs. WPATH SOC 8 will provide guidance in providing that care.

is a clinical professor of psychiatry at UCSF, with a telepsychiatry practice in California. He can be contacted at 

. He spoke at PsychCongress in a presentation titled “Psychiatric Care of Transgender People with Mental Illness and Substance Abuse: New Guidelines from the World Professional Association for Transgender Health Standards of Care Version 8.” The author reports no conflicts of interest concerning the subject matter of this article.

1. Coleman E, Bockting W, Botzer M, et al. Standards of Care for the Health of Transsexual, Transgender, and Gender Nonconforming People, 7th Version. 

 2012;13:165-232. Accessed September 9, 2020. 

2. Karasic DH, Fraser L. Multidisciplinary Care and the Standards of Care for Transgender and Gender Non-conforming Individuals. Schechter L & Safa, B. (Eds.) Gender Confirmation Surgery, Clinics in Plastic Surgery Special Issue. 2018;45(3):295-299. Elsevier,Philadelphia. https://doi.org/10.1016/j.cps.2018.03.016

3. Karasic DH. Protecting Transgender Rights Promotes Transgender Health. 

4. Byne W, Karasic DH, Coleman E, Eyler AE, et al. Gender Dysphoria in Adults: An Overview and Primer for Psychiatrists. 

5. Dhejne C, Lichtenstein P, Boman M, et al. Long-Term Follow-Up of Transsexual Persons Undergoing Sex Reassignment Surgery: Cohort Study in Sweden. 

https://doi.org/10.1371/journal.pone.0016885

6. Dhejne C et al. An analysis of all applications for sex reassignment surgery in Sweden, 1960-2010: prevalence, incidence, and regrets. 

7. Branstrom R, Pachankis R. Reduction in Mental Health Treatment Utilization Among Transgender Individuals After Gender-Affirming Surgeries: A Total Population Study. 

https://doi.org/10.1176/appi.ajp.2019.19010080

8. Correction to Branstrom and Pachankis. August 1, 2020. 

https://doi.org/10.1176/appi.ajp.2020.1778correction

9. What We Know. What does the scholarly research say about the effect of gender transition on transgender well-being? Cornell University Public Policy Research Portal. Accessed September 9, 2020. 

https://whatweknow.inequality.cornell.edu/topics/lgbt-equality/what-does-the-scholarly-research-say-about-the-well-being-of-transgender-people

Experts in transgender health from around the world are participating in and making more sweeping efforts to streamline mental health care for all sectors of the population.

Transition Care for Transgender Patients With Psychiatric and Substance Use Disorders

From randomized trials, clinicians can take away a number of general principles to help guide the process of constructing a “profile” for optimal candidacy with one treatment relative to another.

Joseph F. Goldberg, MD, provides tips to tailoring treatment of mood disorders using a measured approach.

is clinical professor of psychiatry, Icahn School of Medicine at Mount Sinai, New York. The author reports the following disclosures: Abbvie Pharmaceuticals: Speakers Bureau; American Psychiatric Publishing: Royalties; BioXCel: Consultant; Intra-cellular Therapies: Speakers Bureau; Neurocrine: Consultant; Otsuka: consultant; Sage Pharmaceuticals: Consultant; Sunovion: Consultant, Speakers Bureau. Dr Goldberg spoke at 

in a presentation titled “Tailoring Individualized Pharmacotherapy for Bipolar Disorder: How to Translate Findings from Clinical Trials to a Single Patient.”

Tips to tailoring treatment of mood disorders using a measured approach. 

Assessing the Literature for Optimal and Individualized Treatment

Slideshows

Baseline factors that can influence treatment outcomes in psychiatric treatment.

10 Factors That Influence Treatment Outcomes

“It is much more important to know what sort of a patient has a disease

than what sort of disease a patient has”

Imagine devising a pharmacotherapy regimen for each and every patient you see with the same kind of individualized precision and artisanal craftsmanship that an expert tailor uses to create a bespoke suit of clothing. Clinicians sometimes merely equate “personalized medicine” with biomarkers (such as pharmacogenetics), dismissing most other aspects of pharmacotherapy decision-making as largely a trial-and-error process. Yet, when one considers the numerous other clinical, demographic and psychosocial factors that impinge on how any given psychiatric disorder presents, it is not hard to reframe Sir William Osler’s aphorism about “what sort of patient has a disease” as a reckoning of clinical diversity (or what geneticists might call phenotypic heterogeneity).

Rather than simply matching a treatment (say, lithium or divalproex) to a disease state per se (say, bipolar mania), modern psychopharmacology can draw in a much more nuanced fashion from randomized trial data to predict the chances for success with one treatment (or combination) relative to another, based on the presence or absence of key clinical characteristics. “Tailored” pharmacotherapy, informed by the clinical trials literature, involves assessing patient-specific characteristics in order to make reasonable predictions about what treatment or drug combinations have clear rationales and likelihoods for successful outcomes for any one given patient, rather than for a broad diagnosis per se.

In the case of bipolar disorder, clinical diversity is more common than rare. Consider its multitude of contributing factors: patients can manifest pure or mixed mood states, with persistent or undulating symptoms, varying levels of severity and residual symptoms, with or without psychosis, often colored by comorbid medical or psychiatric conditions and personality traits. Bipolar I versus II disorders may differ in symptom profiles (as in depression-proneness or suicide risk) and treatment response (as in the case of 

Some affective or psychomotor symptoms may be more prominent than others; and features such as impulsivity, aggression, suicidality, trauma, cognitive dysfunction, and circadian rhythm disturbances often pose their own conspicuous treatment targets. Tailored approaches also take into account the impact of factors called 

 that can either enhance or derail an otherwise efficacious treatment once it is begun—such as drug adverse effects, treatment adherence, drug-drug interactions, new substance misuse, strength of the therapeutic alliance, or loss of patient insight about the need for ongoing treatment. Biostatisticians call baseline factors that can influence outcome 

Profiling patient candidacy for a given treatment

From randomized trials, one can take away a number of general principles to help guide the tailoring process of constructing a “profile” for optimal candidacy with 1 treatment relative to another. For example:

• Divalproex may yield a better response than lithium in mania involving mixed (rather than pure manic) episodes,

• The combination of lithium plus divalproex seems better than divalproex alone in rapid cyclers

 or during relapse prevention following a 

• Comorbid anxiety symptoms have been shown to improve during treatment for bipolar depression with each of the four existing FDA-approved agents for bipolar depression. Co-therapy with gabapentinoids offers a rationale-based further anxiolytic approach. With the exception of paroxetine, the anxiolytic properties of SSRIs in bipolar patients are largely unknown and cannot be assumed.

• Lithium may warrant independent consideration for its apparent anti-impulsivity effects in patients at risk for acting on suicidal thoughts.

• Among second-generation antipsychotics (SGAs), there is tremendous variability in efficacy (or lack thereof) for bipolar depression. Aripiprazole, ziprasidone, and risperidone have only negative randomized trials in bipolar depression. Relative to quetiapine or olanzapine-fluoxetine combination, lurasidone and cariprazine are the more weight- and metabolically neutral SGAs FDA-approved for bipolar depression; all 4 exert large effects in bipolar depression, so how else do they differ? Lurasidone lacks data in mania and failed to show value for relapse prevention, but it has demonstrated cognitive benefits.

 Cariprazine, by contrast, treats both manias and depressions and its high affinity for D3 dopamine receptors makes it an attractive option in the setting of low motivation and reward. Its potential value for relapse prevention is unknown. Both lurasidone and cariprazine pose concerns for dose-related akathisia and EPS, suggesting that low doses often may be more useful and tolerable than high doses.

• Beyond 6 months after a manic episode, continuing an SGA 

 mood stabilizer may add no greater value for relapse prevention than an antimanic mood stabilizer 

How trial designs tweak the pharmacology evidence-base

Understanding how clinical trial designs affect study findings is another key aspect of using evidence-based data when crafting a bespoke treatment regimen. An important example involves recognizing 

 as a moderator that can inflate placebo response and obscure true drug advantages. One of the best illustrations of this was the failure of lamotrigine to outperform placebo in FDA trials of acute bipolar depression—likely not so much because the drug was ineffective (and having nothing at all to do with lamotrigine’s titration schedule), but rather, because the placebo response rate was inordinately high among low baseline severity patients.

 By contrast, in patients with high baseline severity, a much lower placebo response rate allowed clear separation of drug effect from placebo.

So what does this mean for the practitioner, who is otherwise left thinking only that lamotrigine is just “a mood stabilizer” that’s sometimes used off-label to treat bipolar depression? Quite a bit: the evidence base for lamotrigine shows that it does exert efficacy in bipolar depression, but the unexpectedly high placebo response rate in pivotal trials (due at least partly to low baseline severity) clobbered any meaningful difference between it and active drug. Meanwhile, other studies have shown lamotrigine to synergize with lithium or quetiapine, consequently relegating it to an often more ambiguous role in treating acute bipolar depression.

Antidepressants: bespoke or “unspoke”?

What about antidepressants in bipolar depression—an area that remains mired more in controversy and strong opinion than extensive evidence? Most modern antidepressants (those developed after 1999) have never been formally studied versus placebo in bipolar depression, making them 

 experimental options. Much-publicized concerns that antidepressants are mainly “hazardous” for inducing mania or cycle acceleration run counter to prospective studies that report only about a 12% incident rate of antidepressant-induced mania.

Popular admonitions that antidepressants as a class are ineffective for bipolar depression come from scant placebo-controlled trial literature involving mostly older studies of paroxetine. Fluoxetine (either combined with lithium or olanzapine, or even as monotherapy in bipolar II depression) and sertraline (in bipolar II depression; reviewed by Goldberg1) actually both are among the more evidence-based treatment options in bipolar depression. Antidepressant “candidacy” in bipolar depression is favored by the profile of characteristics listed in 

Perhaps the strongest moderator of a successful outcome is a marked acute response, which tends to predict a better enduring effect with minimal risk for mood destabilization; by contrast, a partial or weak acute response bodes poorly. Importantly, less than one-third of patients with bipolar depression display strong antidepressant responses to modern studied antidepressants (ie, sertraline, venlafaxine, or bupropion). And, similar to unipolar depression, chances for responsivity drop precipitously with each successive failure.

Final considerations: pharmacological parsimony

A third or more of individuals with bipolar disorder take 3 or more psychiatric drugs;12 therefore, let each one count purposefully. Elegance comes from targeting multiple treatment domains with the fewest agents or capitalizing on known synergies while avoiding mechanistic redundancies. Divalproex, for instance, may represent the treatment of choice in a mania-prone male patient with migraine headaches, impulsive aggression, and alcohol use disorder. 

Bupropion could be a handy intervention for a patient with bipolar II pure-depression, prone to nonmixed depression-polarity who is also overweight, smokes, and has attentional complaints. (Ar)modafinil or lisdexamfetamine added to an antimanic drug may neatly address bipolar depression, anergia, and attentional complaints, while the latter may additionally help to manage binge eating or overweight. Every component of a treatment regimen should have a definable purpose; agents deemed ineffective after an adequate trial warrant deprescribing; and decisions about sequential pharmacotherapies are in turn best guided by a careful assessment of patients’ moderating features alongside an informed knowledge of the existing clinical trials literature.

is clinical professor of psychiatry, Icahn School of Medicine at Mount Sinai, New York. The author reports the following disclosures: Abbvie Pharmaceuticals: Speakers Bureau; American Psychiatric Publishing: Royalties; BioXCel: Consultant; Intra-cellular Therapies: Speakers Bureau; Neurocrine: Consultant; Otsuka: consultant; Sage Pharmaceuticals: Consultant; Sunovion: Consultant, Speakers Bureau. Dr Goldberg spoke at PsychCongress 2020 in a presentation titled “Tailoring Individualized Pharmacotherapy for Bipolar Disorder: How to Translate Findings from Clinical Trials to a Single Patient.”

Determining patient candidacy for antidepressant use in bipolar disorder

2. Sajatovic M, Forester BP, Tsai J, et al. Efficacy oflurasidonein adults aged 55 years and older with bipolar depression: post hoc analysis of 2 double-blind, placebo-controlled studies. 

3. Grof P, Duffy A, Cavazzoni P, et al. Is response to prophylactic lithium a familial trait? J Clin Psychiatry. 2002;63(10):942-947.

4. Swann AC, Bowden CL, Morris D, et al. Depression during mania: treatment response to lithium or divalproex. 

5. Swann AC, Bowden CL, Calabrese JR, et al. Differential effect of number of previous episodes of affective disorder on response to lithium or divalproex in acute mania. 

6. Salloum IM, Cornelius JR, Daley DC, et al. Efficacy of valproate maintenance in patients with bipolar disorder and alcoholism: a double-blind placebo-controlled study. 

7. Calabrese JR, Shelton MD, Rapport DJ, et al. A 20-month, double-blind, maintenance trial of lithium versus divalproex in rapid-cycling bipolar disorder. 

8. Geddes JR, Goodwin GM, Rendell J, et al.

 Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised, open-label trial

9. Yatham LN, Mackala S, Basivireddy J, et al. Lurasidone versus treatment as usual for cognitive impairment in euthymic patients with bipolar I disorder: a randomised, open-label, pilot study. 

10. Yatham LN, Beaulieu SchafferA, et al. Optimal duration of risperidone or olanzapine adjunctive therapy to mood stabilizer following remission of a manic episode: a CANMAT randomized double-blind trial. 

11. Geddes JR, Calabrese JR, Goodwin GM. Lamotrigine for treatment of bipolar depression: independent meta-analysis and meta-regression of individual patient data from five randomised trials. 

12. Goldberg JF. Complex combination pharmacotherapy for bipolar disorder: knowing when less is more or more is better. 

The author discusses evidence-based treatment, highlighting clinical trials that support specific uses and patterns of efficacy. 

Bespoke Psychopharmacology for Bipolar Disorder: An Individualized Patient Approach

Melatonin is ubiquitous. It is present in nearly all life forms, including plants and animals, and even single cell organisms. Evolutionarily, it dates back billions of years serving essential cellular processes with its antioxidant and free radical scavenging functions, and more recently as a 

 in the regulation of circadian rhythms and the sleep-wake cycle.

 As humans, we benefit from our endogenous melatonin in support of our complex cellular activity and in helping to orchestrate wide-ranging physiological processes influenced by our circadian system.

 We are not conscious of most melatonin actions, but certainly experience its effects on sleep and waking.

It is useful to think of our endogenous melatonin in 2 ways: 1) reactions occurring intracellularly that do not necessarily involve specific melatonin receptors and 2) the more familiar circadian role associated with regular changes in circulating melatonin and effects on melatonin receptors. Although present in a variety of tissues, circulating melatonin is predominantly produced in the pineal gland under the control of the master 

 transcription-translation loops in the hypothalamic suprachiasmatic nucleus (SCN), which is entrained by exposure to the light-dark cycle.

Normally, plasma melatonin levels are very low during the daytime and gradually rise in the evening as bedtime approaches, typically about 2 hours before a person’s natural sleep onset time; however, the actual clock time of the melatonin rise can vary considerably among individuals. Melatonin production also can be suppressed by light exposure, so this can be a factor affecting the circulating levels and sleep patterns. Usually melatonin plateaus at a relatively high level throughout the night and then declines by morning. When the pineal gland produces melatonin, it is immediately released into the bloodstream and cerebrospinal fluid. This pattern of markedly elevated melatonin levels during the nighttime has led to its description as the “hormone of darkness.” Note that the production of melatonin is primarily under circadian control: while bright light during the nighttime time will suppress it, darkness during the daytime will not turn it on.

The circulating melatonin levels provide the body’s physiology with a clock and a calendar. Changing melatonin concentrations reinforce circadian activity in nearly all tissues and the changing duration of nighttime melatonin secretion reflects the time of year, especially important for seasonally breeding species.3 As humans, our ability to fall asleep at our typical bedtime and the robustness of our circadian cycle are both reinforced by melatonin interacting with the MT1 and MT2 receptors that are highly concentrated in the SCN. The normally coordinated functioning of homeostatic and circadian processes promotes our nighttime sleep of about 8 hours and our daytime-evening wakefulness of about 16 hours.

From late afternoon into the evening, the SCN-driven circadian system produces arousal that counters the homeostatic sleepiness that has accumulated since the morning awakening, thus allowing sustained functioning into the evening. Typically, we are the most alert in the early evening than any other time of the day or night. With approaching bedtime, the rising melatonin agonist activity at the SCN melatonin receptors decreases the stimulation, leaving the homeostatic sleepiness unopposed, thus facilitating bedtime sleep onset. It is notable that the melatonin action is not sedation, but rather a reduction in the evening circadian arousal.

In everyday life, we think of melatonin as a widely available, fairly benign, and maybe helpful sleep aid product. In the United States, it is categorized as a dietary supplement, although in some countries it requires a prescription. Unlike official over-the-counter (OTC) products, which are highly regulated (composition, manufacturing, indications, labeling, and marketing), dietary supplements have little oversight. Studies analyzing consumer melatonin products have shown varying amounts of the compounds, as well as the presence of other unlabeled and sometimes surprising ingredients.

Does exogenous melatonin taken as a dietary supplement enhance sleep? Is it safe?

There is a reasonable argument that taking evening melatonin might augment the natural process of reducing circadian arousal to help people fall asleep more quickly. In general, meta-analyses and systematic reviews of evening melatonin doses compared with placebo show statistically significant improvements in sleep onset that are of questionable clinical 

 Studies have shown little or no benefit for sleep maintenance or total sleep time. The best evidence is for people having a circadian rhythm phase delay (“night owls”), blind individuals with the non-24-hour sleep-wake rhythm disorder, and some children with neurodevelopmental disorders.

 However, much of the research with melatonin has been with few subjects, mixed clinical populations, and for short durations, all limiting the quality of the evidence.

Clinical trial assessments of melatonin safety share the same study limitations, so high-quality data are not available. The more common adverse event reports include daytime drowsiness and nightmares, though the rates are low. Generally, melatonin is well tolerated in these placebo comparison studies with typical consumer product doses.

A darker side of both endogenous and exogenous melatonin has been emerging in recent years with investigations of circadian rhythms and 

, specifically examining glucose tolerance, insulin release and sensitivity, weight gain, and the timing of food intake.

 The circadian regulation of metabolism is just right for people who are active, get plenty of light exposure, and have their meals during the daytime, and who are in the dark sleeping during the nighttime. In our society, many people eat at irregular times, including late in the evening and during the night, when our circadian system expects us to be fasting. An evening meal will result in higher glucose and insulin levels compared with the identical meal eaten early in the day. Over time these elevated evening glucose and insulin levels increase the risk for obesity and type 2 diabetes mellitus. The timing of food intake in relation to our evening melatonin rise appears to be an important factor.

 studied the sleep-wake patterns of healthy young adults over a 30-day period that included 1 week of monitoring the timing and content of all food they ate, and also an overnight laboratory assessment of their melatonin patterns and body composition. They found a significant relationship between the timing of food consumption relative to melatonin onset and the percentage of body fat and body mass index, controlling for the actual clock time, caloric amount, activity or exercise level, and sleep duration. Eating food later in the day had a detrimental effect.

These findings are consistent with studies demonstrating the weight loss and metabolic benefits of time restricted eating routines where people consume their meals on a relatively early schedule and fast through the evening and nighttime. Avoiding evening eating close to and following our melatonin rise appears to have advantageous metabolic effects.

If we should avoid eating and digesting food close to our evening endogenous melatonin rise, what are the implications for using exogenous melatonin as a sleep aid? There is evidence that taking melatonin also leads to impairment in glucose tolerance. Rubio-Sastre and colleagues

 studied 21 healthy women, giving them either melatonin 5 mg or a placebo in the morning and evening on different days. An oral glucose tolerance test monitoring glucose and insulin levels for 3 hours began 15 minutes after each dose. Finding that the melatonin use was associated with elevated glucose levels at both time points, they concluded that the optimum timing for melatonin doses should be at least 2 hours after the last meal.

Perhaps the best plan for melatonin to help with sleep is to give our own circadian rhythm and melatonin release a chance to do the job.

 Maintaining regular sleep-wake hours, plenty of daytime activity and light exposure, and early meal timing should aid in stabilizing the circadian cycle. Avoiding bright light in the evening for a few hours prior to bedtime should limit the suppression of melatonin, especially if using reddish low color-temperature lighting, now readily available with LED products. Using electronic screens (eg, phones, tablets, laptops) held close to the face should be limited as bedtime approaches—even when using those devices with blue spectrum-blocking apps or filters. These good sleep habits that facilitate earlier and higher melatonin release may be the solution to achieve an earlier sleep onset.

If one is inclined to take a dose of melatonin to enhance sleep, it probably will help the most when taken prior to bedtime, but ideally well after the last meal.

 Even very low doses result in blood levels hundreds to thousands of time higher than the normal endogenous circulating amount. Low doses should be as effective as high doses, since the primary action of melatonin is not sedation. The ultimate benefit in helping people fall asleep more quickly may take several days or weeks as melatonin advances and stabilizes the circadian system.

The bright side of this “hormone of darkness” is the extraordinary roles it serves in stabilizing our cellular and circadian functioning. If we manage to live our lives closer to our natural circadian physiology, we can avoid melatonin’s potential metabolic darkness.

is associate professor in the Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD. He spoke at PsychCongress 2020 in a presentation titled Melatonin: What, Why, and Why Not? The author reports he is a consultant with Eisai Inc and Abbott Laboratories.

Melatonin synthesis and function: Evolutionary history in animals and plants

2. Claustrat B, Leston J. Melatonin: Physiological effects in humans. 

3. Arendt J. Melatonin: Countering chaotic time cues. 

Our own melatonin plays an important role in regulating our sleep-wake cycle. Recent evidence raises questions about whether we should be taking extra doses to try to improve our sleep. 

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