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(This is the third part of the How To Diagnose Bipolar Disorder series—Ed.)

Have you had difficulty with differential diagnosis when the patient has manic symptoms and psychosis? In 2013, the DSM-5 made the issue clearer with significant changes in the criteria defining the quantity and nature of mood symptoms in these diagnoses. As a result, more patients will be diagnosed with schizophrenia compared with when using DSM-IV in either the TM or later “Text Revised” TR version. I will propose some of the implications for psychopharmacology.

In the schizophrenia D criteria in DSM-5, the patient should have no mood episodes (ie, meeting full criteria for mania or depression) during the active phase of the illness, or, if the patient has episodes, those episodes occur during a minority (ie, up to 50%) of the total duration of the illness (active and residual phases). In other words, a patient with schizophrenia can have a full manic syndrome present for up to 50% of the time, as long as the other schizophrenia criteria are met. Those criteria include, from the A criteria, positive symptoms during the acute phase; the B criteria of illness duration of at least 6 months of the active and residual phases; the C criteria of deterioration in functioning compared to premorbid levels; and the E criteria of no explanation of it from a substance or medical illness.

In the DSM-IV D criteria for schizophrenia, the requirement was that any mood episodes had to be brief in duration compared with the duration of the illness. An example of “brief” was a 5-week period of mania or depression in a patient who was ill for 4 years, which would translate to having a mood syndrome present 2.5% of the time. So, with DSM-IV, individuals with schizophrenia could not experience much time with any mood syndrome to meet the criteria. If mood syndromes were present longer than 2.5% of the time, the diagnosis would be schizoaffective disorder or bipolar with psychosis.

However, the DSM-5 criteria for schizoaffective disorder offer the mirror image of the D criteria for schizophrenia: Here, the individual must meet criteria for a mood syndrome for the majority (ie, 50% or more) of the total time that they have been ill. In DSM-IV, it had to be substantial (ie, more than brief [2.5%]). Diagnosis also requires the other schizoaffective criteria, including 2 weeks of psychosis in the absence of prominent mood symptoms. Here, the term 

, meaning that there cannot be any prominent symptoms—much less the full syndrome—of mania or depression present for those 2 weeks.

There seem to be very few patients who meet these DSM-5 criteria for schizoaffective disorder, which require that they be in a mania (or depression) for the majority of the time and also have psychosis without any significant symptoms of a mood disorder for 2 full weeks. Making it tougher to diagnose schizoaffective disorder was probably intended by the DSM-5 authors. The evidence they considered suggested that the disorder, as defined in DSM-IV, did not exist;

 they wanted to eliminate it. They retained it because of pushback from field trials, with practicing psychiatrists who largely wanted to keep schizoaffective disorder in the manual.

Notably, study results have shown that when the DSM-IV criteria for schizoaffective disorder were in use (1994-2013), clinicians did not seem to use it for diagnoses.

 They overdiagnosed it using unspecified criteria. Also, study results found that patients diagnosed using the criteria very often evolved over time to having a schizophrenia diagnosis, whereas schizophrenia diagnoses under DSM-IV tended to be stable over time.

 Accordingly, with the new, more inclusive DSM-5 criteria for schizophrenia, the diagnosis should continue to be stable.

How about the diagnosis of mania with psychosis? In psychotic mania (in DSM-IV and DSM-5), the psychosis appears only during the time the patient is meeting criteria for mania, not after it as in schizoaffective disorder. Usually, the psychosis develops during the most severe part of the mania and tends to resolve early as the episode improves, and before the rest of the manic symptoms resolve.

Now that you have an accurate diagnosis per DSM-5, what is the psychopharmacology treatment? If the diagnosis turns out to be schizophrenia, there is no demonstrated value to adding non-antipsychotic mood stabilizers (like lithium or valproate) to the antipsychotic for the manic component, according to the evidence reviewed in the Schizophrenia Patient Outcomes Research Team (PORT) guidelines.

 These additions only potentially contribute adverse effects. The usual psychopharmacology algorithm of employing 2 adequate monotherapy trials of antipsychotics followed by consideration of clozapine probably still applies for DSM-5 schizophrenia. If the diagnosis is bipolar with psychosis, you can use those traditional mood stabilizers as well as antipsychotics. Study results show that psychotic mania responds just as well to either class of drugs.

But what if the patient meets the DSM-5 criteria for schizoaffective disorder, bipolar type? We do not know how to treat it, just as we did not know how to treat DSM-IV schizoaffective disorder, bipolar type. There are almost no studies, no algorithms to consult, no FDA-approved options (although some paliperidone products did manage to get the only FDA approval for schizoaffective disorder). There is still serious doubt that the condition even exists as a valid entity, and it is likely that the current criteria capture only some patients who belong in either the schizophrenia spectrum or the bipolar spectrum.

It is suggested that you treat with your best psychopharmacology algorithm for schizophrenia or for bipolar with psychosis, depending on which diagnostic category best represents the patient’s presentation. If the results are unsatisfactory, try switching to your algorithm for the other diagnosis. This may produce better results than improvising with pure guesswork.

is co-director of the VA National Bipolar Disorder Telehealth Program and an associate professor of psychiatry at Harvard Medical School at the VA Boston Healthcare System.

1. Kotov R, Leong SH, Mojtabai R, et al. 

Boundaries of schizoaffective disorder: revisiting Kraepelin

2. Cheniaux E, Landeira-Fernandez J, Lessa Telles L, et al. 

Does schizoaffective disorder really exist? a systematic review of the studies that compared schizoaffective disorder with schizophrenia or mood disorders

Current issues on schizoaffective disorder

4. Jäger M, Haack S, Becker T, Frasch K. 

Schizoaffective disorder—an ongoing challenge for psychiatric nosology

The stages of mania. a longitudinal analysis of the manic episode

6. Kreyenbuhl J, Buchanan RW, Dickerson FB, Dixon LB; Schizophrenia Patient Outcomes Research Team (PORT). 

The Schizophrenia Patient Outcomes Research Team (PORT): updated treatment recommendations 2009

The psychopharmacology algorithm project at the Harvard South Shore Program: an algorithm for acute mania

Have you had difficulty with differential diagnosis when patients have manic symptoms and psychosis? One doctor discusses the related DSM-5 criteria changes and some of their implications for psychopharmacology.


Mania With Psychosis vs Schizophrenia vs Schizoaffective Disorder, Bipolar Type

A survey of individuals living with bipolar I disorder revealed these individuals’ perspectives on medication and treatment of the disorder.

The survey polled 305 US individuals aged 18 to 60 living with bipolar I disorder

 about their experiences living with and receiving treatment for the disorder. Among the participants, the average age of diagnosis was 28 years, and the average length of time participants had been living with the disorder was about 16 years.

In terms of everyday impact, 81% of participants reported feeling like no one understands what they go through in living with bipolar I. Top concerns participants reported about managing the disorder included motivation/energy to do things they enjoy (28%), quality of sleep (28%), and frequency of depressive episodes or symptoms (27%). Among those who have attended school or been employed, 77% said living with the disorder makes them feel alone or isolated; 51% said the disorder makes them less productive at school and/or work; and 47% have tried to hide their condition from classmates or colleagues.

Participants were also asked about their experiences with receiving treatment for bipolar I, with 70% reporting that finding a medication that works for them has been difficult, and 54% and 17% reporting that they have tried more than 5 or more than 10 medications, respectively. Ninety-three percent of participants said they had experienced side effects from medication. The most commonly reported side effects included anxiety (56%), weight gain (56%), and sleepiness/drowsiness (53%). Of the participants who reported having experienced side effects, 95% said that the side effects had a negative impact on their daily lives, including loss of motivation to do things they enjoy (41%), reduced sleep quality (34%), and reduced sexual function/loss of desire (22%). Overall, 80% of participants said they wished they had treatment options that would relieve their symptoms of bipolar I with fewer side effects. However, 75% reported that they felt well-managed on their current medication regimen.

“Living with and managing bipolar I disorder can be a profoundly challenging experience, but it is important to remember that people with this condition can lead stable, enjoyable, and fulfilling lives,” said Michael Pollock, chief executive officer of the Depression and Bipolar Support Alliance (DBSA), in a press release. “The perspectives shared through this survey by people living with bipolar I disorder underscore the need for effective medications and the importance of considering the unique needs and experiences of individuals living with this disease—whether physical, mental, or social—as people work with their health care providers to evaluate treatment options.”

The survey was conducted by The Harris Poll on behalf of Alkermes Inc. in collaboration with the DBSA.

Living with bipolar I disorder: individuals living with bipolar I disorder (BD-I) shared perspectives on treatment and medication

. Infographic. The Harris Poll. Accessed January 6, 2022.

New national survey of people living with bipolar I disorder provides into disease-related challenges and the treatment journey

. News Release. CISION PR Newswire. January 6, 2022. Accessed January 6, 2022.

Patients weigh in on their experiences living with and receiving treatment for the disorder.

Patients With Bipolar I Disorder Share Perspectives in New Survey

The US Food and Drug Administration (FDA) has approved Caplyta (lumateperone) for the treatment of 

Caplyta, an atypical antipsychotic from biopharmaceutical company Intra-Cellular Therapies, is the only drug approved by the FDA for the treatment of depressive episodes stemming from bipolar I or bipolar II disorder in adults as monotherapy or adjunctive therapy with either valproate or lithium. The drug has shown a consistently favorable profile on weight, extrapyramidal symptoms, and cardiometabolic parameters, according to Sharon Mates, PhD, chairman and CEO of Intra-Cellular Therapies.

The drug was previously approved by the FDA for the treatment of schizophrenia in adults in 2019

 following favorable safety and tolerability as well as demonstrated efficiency among patients with schizophrenia in prior studies. With this expansion of indications, Intra-Cellular Therapies announced that plans to launch its Caplyta treatment for bipolar depression will begin immediately.

This approval is important for individuals living with bipolar depression and their providers, given the limited treatment options for depressive symptoms specifically associated with bipolar disorder. Bipolar depression is the most common and the most significant clinical presentation in individuals with bipolar disorder, which currently affects 11 million adults in the United States.

“The efficacy, and favorable safety and tolerability profile, make Caplyta an important treatment option for the millions of patients living with bipolar I or II depression and represents a major development for these patients. Caplyta is approved for a broad range of adult patients, including those patients with bipolar II depression who have been underserved with limited treatment options,” said Roger McIntyre, MD, FRCPC, professor of psychiatry and pharmacology at the University of Toronto and head of the Mood Disorders Psychopharmacology Unit at the University Health Network, Toronto, Canada, in a press release.

“We are excited to offer Caplyta to the millions of patients living with bipolar depression,” Mates said in a press release. “We thank the patients, health care professionals, and our Intra-Cellular team for all their contributions that led to this approval.”

Intra-Cellular Therapies announces U.S. FDA approval of CAPLYTA (lumateperone) for the treatment of bipolar depression in adults

. News Release. Intra-Cellular Therapies. December 20, 2021. Accessed December 20, 2021.

FDA approves Intra-Cellular Therapies’ novel antipsychotic, CAPLYTA (lumateperone) for the treatment of schizophrenia in adults

. News Release. Intra-Cellular Therapies. December 23, 2019. Accessed December 20, 2021.

Caplyta is now FDA-approved for depressive episodes from bipolar I and II.

FDA Approves New Treatment for Bipolar Depression

 have focused on lithium’s advantages. The well-known downsides, including renal impairment, have also been discussed. However, a recent consultation reminded me that there is an infrequent, but important, toxic effect of lithium that deserves increased awareness: the Syndrome of Irreversible Lithium-Effectuated Neurotoxicity, or SILENT.

 First named in the 1980s, SILENT was diagnosed in 90 case reports in peer-reviewed publications as of 2005, starting in 1949 when lithium chloride was being used as a substitute for table salt.

The clinical profile of SILENT varies, but persistent cerebellar dysfunction is the most common finding, with extrapyramidal symptoms also typically present. Many of these cases involve insidious progression in patients on normal or low therapeutic levels of 

. The first sign may be decreased alertness or slight apathy, followed by muscular rigidity or fasciculations and mild ataxia. These symptoms increase and become severe, and then impaired consciousness with a stupor-like presentation can develop.

When lithium is stopped, some or all of these symptoms may persist beyond 2 months, with some reports describing continued symptoms for 5 years. Most cases have residual impairments such as ataxia and dysarthria that continue for 1 year. Sometimes there is persisting cognitive dysfunction with memory loss and other symptoms of dementia. In other cases, additional atypical symptoms accompany the core features, including nystagmus, papilledema, and choreoathetoid movements suggestive of tardive dyskinesia.

SILENT’s cause is unknown. Demyelination has been found on biopsy of peripheral nerves and may occur in the cerebellum and elsewhere.

 This may account for the persistence of the neurological sequelae.

Precipitating or predictive factors may include diagnosis of schizoaffective disorder, marked psychosis, abnormal EEG prior to treatment, preexisting neurological illnesses including Alzheimer disease, and fever—especially high fever.

 Readers may recall the famous 1970s cases of neurotoxicity arising from the use of lithium plus haloperidol.

 All patients in those cases had very high fevers and high lithium levels, and they are now thought to have had cases of SILENT. Some other possible contributing factors could be hypertension, heart failure, rapid lowering from high lithium levels, and epilepsy.

To prevent SILENT, it may be helpful to avoid high lithium levels through regular and frequent monitoring (eg, every 4-6 months). If symptoms develop, 

. Treat persisting symptoms with appropriate physical rehabilitation and cognitive training as you would for dementia.

The other side of the coin on lithium neurotoxicity, as discussed in a previous column,

 is the positive neurotrophic effects of lithium that benefit many patients. In a recent pilot study, for example, 12 patients recovering from stroke were prescribed open-label lithium for 60 days (target levels, 0.4-0.6 mEq/L). Gray matter volume as measured by MRI increased numerically (but not significantly; P = .07), and there was a significant correlation between higher lithium dose and gray matter volume increase (P = .004) and improved verbal memory (P = .05).

In conclusion, lithium’s benefits to brain health are substantial, but there are rare cases of serious toxicity that should be detected as early as possible.

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.

The syndrome of irreversible lithium-effectuated neurotoxicity. 

2. Hanlon LW, Romaine M III, Gilroy FJ, Deitrick JE. 

Lithium chloride as a substitute for sodium chloride in the diet; observations on its toxicity.

Lithium carbonate, haloperidol, and irreversible brain damage.

5. Sun YR, Herrmann N, Scott CJM, et al. 

Lithium carbonate in a poststroke population: exploratory analyses of neuroanatomical and cognitive outcomes.

This infrequent, but important, toxic effect of lithium deserves increased awareness.

Lithium Neurotoxicity: The SILENT Syndrome

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 

 (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.

When there is a comorbidity, one should first delineate the various DSM-5 diagnoses that are present (

). 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.

 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.

 The first clinical encounter is an important moment that sets the stage for the 

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. 

 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.

 (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 

, but the PTSD symptoms, including irritability, will likely not respond to it, as was demonstrated in 2 negative controlled studies.

 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.

 (ADHD) is another comorbidity with BD. Most adults with ADHD have emotional dysregulation, which presents as chronic over-reactiveness to stresses.

 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.

 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.

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, 

, 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. 

, once again, might be the preferred treatment.

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.

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.

Chemotherapy in Psychiatry: Pharmacologic Basis of Treatments for Major Mental Illness.

Psychopharmacology Algorithms: Clinical Guidance From the Psychopharmacology Algorithm Project at the Harvard South Shore Psychiatry Residency Program.

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.

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.

5. Hamner MB, Faldowski RA, Robert S, et al. 

A preliminary controlled trial of divalproex in posttraumatic stress disorder.

6. Faraone SV, Banaschewski T, Coghill D, et al. 

The World Federation of ADHD International Consensus Statement: 208 evidence-based conclusions about the disorder.

7. Viktorin A, Rydén E, Thase ME, et al. 

The risk of treatment-emergent mania with methylphenidate in bipolar disorder.

Comorbid PTSD: update on the role of prazosin. 

Sorting Out Comorbidities

, Michael Thase, MD; Gustavo Alva, MD, DFAPA; Theresa Cerulli, MD; and Tina Matthew-Hayes, DNP, FNP, PMHNP, shared their insights on the identification and management of bipolar disorder.

“Sometimes people go about without necessarily receiving an appropriate diagnosis for a while,” said Alva, medical director of ATP Clinical Research in Costa Mesa, California. “Based on the literature, sometimes people go 5 to 10 years before asserting the appropriate diagnosis.”

To highlight diagnostic challenges and discuss optimized treatment, the panel walked through 2 interesting case vignettes.

A 27-year-old woman presents for evaluation of a complex depressive syndrome after having failed 2 recent trials of antidepressants. She has a history of attention-deficit/hyperactivity disorder (ADHD), for which she took methylphenidate during her youth. Her depressive episode occurred, as she described it, “right out of the blue.” She is taking sertraline and escitalopram at the time of initial evaluation; and escitalopram was recently reduced by her primary care provider from 20 mg to 10 mg because she believed the medicine might have been making her worse.

The patient’s symptoms include hypersexuality, hypersomnolence, overeating, reactive mood, tearfulness, and trouble concentrating. On the day of her first visit, she scores 16 on the Patient Health Questionnaire-9 (PHQ-9), which is in the moderate depression range. She filled out the mood disorder questionnaire and scored a whopping 10, which is not the highest possible score but higher than 95% of people who take this inventory. The differential diagnosis for this patient included major depressive disorder, recurrent unipolar with mixed features versus bipolar II disorder, with an antecedent history of ADHD. The patient was not taking any mood-stabilizing medication.

“When we consider somebody with a major depressive episode, obviously a differential diagnosis of bipolar disorder and a depressive episode is certainly one that we should be considering. I think that this particular case is quite interesting in that it brings so many different elements to the forefront and helps us along lines of medication misadventures. And the possibility of maybe barking up the wrong tree and not necessarily addressing the underlying issues that we need to be getting to,” Alva said.

One of the complicating factors, as Cerulli explained, is the history of ADHD. “[The patient] has had recurrent depressive episodes with some mixed features that could be mixed up with things like the reactivity of ADHD, the higher energy of ADHD, and the irritability of ADHD—it’s easy to miss that this was actually a bipolar picture,” she said. “We’re really looking at risk factors to be able to help identify who are the patients that are at risk for bipolar as opposed to unipolar depression, or just an ADHD anxious irritable picture, which is so commonly where these folks get lumped into.”

The panel was then asked which treatment option they would be most likely to start with this patient: lithium, quetiapine, divalproex, lurasidone, or cariprazine.

Matthew-Hayes chose cariprazine, based on the metabolic profile, her experience with the medication, and the FDA-approved status for both depression and mania. Alva agreed, noting that cariprazine is not sedating, would not require a food alteration, and has an attractive profile for someone who has the potential to become pregnant.

A 47-year-old male investment banker with a history of manic episodes comes for a second opinion regarding treatment of an intractable depressive episode. His initial treatment was with lithium, which was highly effective, but it aggravated his psoriasis, gave him a low-grade tremor (even at blood level of 0.6 mEq/L), and caused excessive thirst. He was switched to divalproex, which was not as effective. It was supplemented first by olanzapine, then risperidone, and then lamotrigine at the beginning of this episode. Lamotrigine had helped during a previous episode, but this time it did not help enough even when titrated up to 400 mg. Adequate trials of bupropion, fluoxetine, and duloxetine, even at high doses, did not result in a meaningful drop in the PHQ-9 score.

His symptoms included unreactive low mood, pervasive anhedonia, and passive suicidal ideation. He did not have a substance use disorder, nor was he psychotic. The interview indicated he was adherent to the treatment.

Based on the data presented, this patient meets the definition of treatment-resistant depression and bipolar I depression, for which there is only a single treatment indicated: the combination formulation of olanzapine and fluoxetine. Because of the metabolic risks associated with olanzapine, this treatment is not ideal.

Another strategy might be to add lithium to the current mood stabilizer combination, but the patient had tolerability issues with this medication. Other options include newer-generation antipsychotics, with quetiapine, lurasidone, and cariprazine having FDA approval for bipolar I depression.

After discussion, the panel thought cariprazine would be the best next option. “With cariprazine being FDA approved for treating all phases of bipolar—bipolar depression, mixed phase, and manic symptoms—you get a little assurance that you’re not going to end up triggering the manic symptoms. You may, in fact, be also treating and preventing the other phases of bipolar simultaneously, while treating this very treatment-resistant depression phase that the patient is in,” Cerulli said.

In addition, the panel discussed the positives of telemedicine in the struggle to identify and treat bipolar disorder.

“It’s a wonderful opportunity to be able to reach patients that we might not otherwise have been able to reach,” Cerulli said. “I found that this has been a nice way to be able to see patients that are at a distance from practice that I can now have an opportunity to work with.”

Matthew-Hayes added that telemedicine helps to keep matters confidential: “One of the other huge benefits is getting some of our patients, especially bipolar patients, a little more privacy.”

Matthew-Hayes also suggested reaching out to local National Alliance on Mental Illness organizations to help get patients the internet access at decreased rates so they can use telehealth appointments. Thase recommended checking out the Depression and Bipolar Support Alliance, of which he is a 30-year member, where largely free psychoeducational resources can be found. 

is professor of psychiatry at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia.

is medical director of ATP Clinical Research in Costa Mesa, California. He also works with Avanir, Otsuka, ACADIA, Lundbeck, Abbvie, Teva, Neurocrine Biosciences, Athira, Liva-Nova, and Alector.

is the medical director of Cerulli and Associates in North Andover, Massachusetts. She also works with Abbvie and is a speaker for Vraylar. 

is a dual certified nurse practitioner at the Western Pennsylvania Behavioral Health Resources in West Mifflin, Pennsylvania. 

Need a recap of the custom Around the Practice video program on bipolar disorder? We've got you covered. 

Bipolar Disorder: The Difficult Diagnosis 

Three Myths About Bipolar Disorder

Don't fall into the trap of these 3 myths about mania in bipolar disorder...

Roger S. McIntyre, MD, FRCPC, of the University of Toronto and the University Health Network presented on inflammation in individuals with mood disorders at the 2021 Neuroscience Education Institute (NEI) Congress Friday, November 5, in Colorado Springs, Colorado.

In his presentation, titled “Inflamed in the Brain: The Role of Inflammation in Psychiatry,” McIntyre discussed the physiology of the inflammatory system and how inflammation correlates in individuals with mood disorders, as well as some common anti-inflammatory interventions for these individuals. He stated that there is a high prevalence of inflammation in individuals with mood disorders such as depression and bipolar disorder: About 25% to 30% of individuals with major depressive disorder (MDD) or bipolar disorder have a CRP of higher than 3 mg per liter, and 50% have a CRP of higher than 1. Using COVID-19 as an example, he reported that individuals with MDD or bipolar disorder were more likely to contract, be hospitalized, and die due to COVID-19. Further, one-third of outpatients and one-half of inpatients with COVID-19 have since developed a neurologic or psychiatric disorder.

McIntyre shared that some sources of pro-inflammatory balance in mood disorders include genetics, as well as environmental factors like social determinants (eg, poverty), behavior (eg, smoking cigarettes), diet, sleep disturbance/chronobiology, comorbidity (eg, obesity), microbiota, trauma, and loneliness. He also recommended several anti-inflammatory treatment methods, including mindfulness, exercise, restorative sleep, Mediterranean-like diet, and greater social network ties.

According to McIntyre, having an increased understanding of the link between inflammation and psychiatric disorders has become particularly important, given the association between COVID-19 and mood disorders.“We have a serious public health crisis right now,” he said during his presentation. “We all want to see our patients get vaccinated to protect their health … but I think we have to advocate for our patients. And we have to be very vigilant because I don’t think we know if a year from now—or 2 years from now or 3 years from now—whether the immunocompetence can be assumed to be identical. I don’t know the answer to that. It’s a really interesting hypothesis that if we can better treat them with psychotherapy, CBT, mindfulness, and good antidepressants they can tolerate, this might be the extra boost they need.”

McIntyre is a professor of psychiatry and pharmacology at the University of Toronto and head of the Mood Disorders Psychopharmacology Unit at the University Health Network in Toronto, Canada. In his research, he aims primarily to characterize the neurobiology, phenomenology, and novel therapeutics of mood disorders.

1. McIntyre RS. Inflamed in the brain: the role of inflammation in psychiatry. Presented at 2021 NEI Congress. November 5, 2021.

What is the connection between inflammation and mood disorders?

Inflamed in the Brain

Although the DSM-5 diagnostic criteria for a major depressive episode are the same for unipolar and bipolar disorders, these episodes differ in their natural past history (ie, patients with bipolar disorders will have discrete episodes of hypomanias or manias), age of onset, suicide risk, associated comorbidities, and biological correlates. And, most importantly, they differ dramatically in the medications that are effective. Thus, it is critical to diagnose them correctly.

To do so, you must take a good history for 

, because this is where diagnostic error commonly occurs. Start by informing the patient how important it is to have the correct diagnosis for effective treatment and that being wrong about the diagnosis can lead to the wrong treatment—which is at best ineffective and at worst very harmful (eg, antidepressants can cause a malignant transformation in bipolar disorder to a rapid cycling and treatment-resistant condition).

 This warning to the patient hopefully overrides their potential reluctance to disclose manic symptoms because of the stigma of the diagnosis, their enjoyment of the experience, or their belief that it represents their normal mood and energy that they would like to return to and maintain.

 or hypomania. Patients often wake up feeling, for no particular reason, unusually energetic, with thoughts racing about millions of things they want to get done. They want to start new projects, clean and organize the house, add to their possessions, contact neglected friends. They set out to do those projects and then they go-go-go day and night, feeling a lessened need for sleep or maybe skipping sleep completely for a night or so. They almost invariably spend money to fund the ventures or add to hobbies, clothes, or possessions. Often, they already have plenty of what they are buying and they later recognize that the purchases were unnecessary. They discount the importance of other bills, thinking they will figure out how to pay those at some future date, believing the new purchases to be more important.

Explain that during mania their speech is accelerated and increased in quantity and volume. This tends to be noticed by others, who will advise them to “slow down” so they can be understood. Friends and family may see their plans as impractical, unrealistic, or risky, but patients in the grip of mania will ignore this feedback and often lash out and become irritable and defensive. At work, if there are disagreements with the boss, there can be loud arguments, and the person with mania can impulsively quit or get fired, which they later regret.

Their disinhibited speech can also include embarrassing self-disclosures, undiplomatic criticisms of others, or inappropriate sexualized content. Their property can be littered with tools and supplies for projects that were never finished, because when the manic episode ends, they lose all interest in the activity. Parts of their house may be partly demolished in preparation for the project and then stay that way for years, because when the next manic episode begins, they usually start an entirely different project. Make it clear to the patient that the episodes you are talking about last at least a few days and nights, often more.

At this point, stop and see if the patient recognizes these behavioral patterns. If it is unclear, bring up some additional symptoms: social overactivity, hazardous driving patterns, uncharacteristically starting conversations with strangers, and commonly sexual preoccupations and overactivity (this is a cause, although not the only one, of infidelity in established relationships, often resulting in the end of the primary relationship). It is often best to leave inquiries about sexual indiscretions to a later time due to possible embarrassment for them, but by the time you bring it up, you might get a very emphatic response of “absolutely!” about this symptom.

If the patient reports that these events do occur, get details about how long they last, how frequently the behaviors occur, and whether they cause significant impairment in social or work relationships, have legal consequences, or result in financial hardship. This will determine whether the patient meets the criteria for bipolar I or II, and rapid versus nonrapid cycling.

If the patient does not report criteria-meeting manic episodes, it is possible that they have prebipolar depression and could have a hypomanic or manic episode in the future.

 Initial manias have occurred in elderly patients after decades of depressions. A number of factors may predict when a unipolar major depressive disorder diagnosis could change to a bipolar disorder (

 If enough predictors are present, including failure on previous antidepressant trials, consider treating the depression as a 

 and taper off any antidepressants as you do so.

is associate professor of psychiatry at Harvard Medical School and co-director, US Department of Veterans Affairs National Bipolar Disorders Telehealth Program. The author reports no conflicts of interest concerning the subject matter of this article.

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3. El-Mallakh RS, Vöhringer PA, Ostacher MM, et al. 

Antidepressants worsen rapid-cycling course in bipolar depression: a STEP-BD randomized clinical trial.

4. Faedda GL, Baldessarini RJ, Marangoni C, et al. 

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Major depressive episode and bipolar disorders: same DSM-5 diagnostic criteria, but very different disorders. 

Bipolar Depression: How Not to Miss the Diagnosis

Michael E. Thase, MD; Theresa Cerulli, MD; Gustavo Alva, MD, DFAPA; and Tina Matthews-Hayes, DNP, FNP, PMHNP, provide insight on the role of telemedicine in improving outcomes for patients with bipolar disorder.

Bipolar Disorder