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“Ms Lena” is a 60-year-old African-American female with a 20-year history of bipolar I disorder. Her most recent episode featured depression without psychosis, and she is seen for monthly outpatient visits. She had a history of thyroid dysfunction and had a thyroidectomy at age 25 years. She currently takes 175 mcg levothyroxine for thyroid replacement. She has had no psychiatric hospitalizations in the past 15 years, but has chronic, mild depression. She took lithium briefly in the past, but her current psychotropic medications include risperidone and oxcarbazepine. Her most recent thyroid function was notable for elevated TSH (10.67 mcIU/mL), but normal free T4 (1.15 ng/dL) and T3 (0.64 ng/mL). As her psychiatrist, do you think changes in her thyroid function tests are associated with changes in mood state?

Fluctuations in mood state in bipolar disorder may be spontaneous or associated with psychological and/or pharmacologic factors. Lithium, along with key treatment option for bipolar disorder, is known to affect thyroid function.

 Low thyroid function may be associated with bipolar depression.

 Hospitalized patients with bipolar depression and low baseline thyroid-stimulating hormone (TSH) levels are more likely to switch to mania.

 Thyroid dysfunction is also associated with poorer treatment response in bipolar disorder.

 investigated thyroid function in drug-naïve patients with bipolar disorder, considering effects of current mood state. They recruited inpatients from the West China Hospital from December 2018 to December 2019. Indices of thyroid function included TSH, free and total T3 and T4 (FT3, TT3, FT4, and TT4), as well as the rate of thyroid hormone secretion. 

Inclusion criteria were that participants must be aged 18 to 65 years and drug-naïve before hospitalization, with a discharge diagnosis of ICD-10 bipolar disorder. Exclusion criteria were psychiatric comorbidity, serious physical illness, autoimmune disorders, pregnancy or lactation, and history of thyroid disease. Symptoms were assessed with the Montgomery-Asberg Depression Scale (MADRS) and the Young Mania Rating Scale (YMRS). Data were analyzed with ANOVA or χ2 tests.

The authors included 291 patients (136 with mania, 128 with depression, and 27 with mixed). The mean participant age was 27 years, the mean illness duration was 6.7 years, and 48% were male. Subjects were further subgrouped based on severity of mania or depression, and the presence or absence of psychosis. There were no significant differences in age, sex, education, or other demographic variables by the main diagnostic subgroups (mania, depression, and mixed). There were no differences in TSH, TT3, TT4, and FT4 by diagnostic subgroups.

However, there were significant differences in FT3 levels among the diagnostic subgroups, with higher levels in mania versus depression (mean 8.1 versus 4.3 pmol/L). Concomitantly, there was also difference in the incidence of increased rate of thyroid hormone secretion in mania versus depression (20.6 versus 1.6%). Finally, there was a difference in the incidence in the total abnormality rate of thyroid hormone secretion in mania versus depression (69.9 versus 45.3%). There was a small but significant correlation between FT3 levels and YMRS total score in patients with bipolar mania (r=0.18). By contrast, there were no correlations between symptoms and FT3 levels in patients with bipolar mixed or depression.

The authors concluded that in drug-naïve patients with bipolar mania, FT3 levels are higher, and rates of abnormal thyroid hormone secretion are higher than in patients with bipolar depression. FT3 levels were significantly positively correlated with the severity of mania. 

The primary study strength was that subjects were drug-naïve, which means findings are independent of the effects of psychotropic medications. Study limitations included the cross-sectional design and assessment of thyroid indices at a single time point, which precluded inferences regarding causality. The authors also did not screen for thyroid autoantibodies. The small number of subjects in the bipolar mixed subgroup also limited statistical power for between-group comparisons.

There is evidence for more severe thyroid axis dysfunction in patients with bipolar mania versus depression. Thyroid hormone levels may contribute to mood changes in bipolar disorder, which should be assessed in prospective studies. Primary prevention, screening, and treatment efforts are needed for this patient population to mitigate increased cardiovascular disease morbidity and mortality.

is a professor in the Department of Psychiatry and Health Behavior at Augusta University in Augusta, Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for 

The author reports that he receives research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute.

1. McKnight RF, Adida M, Budge K, et al. 

Lithium toxicity profile: a systematic review and meta-analysis

2. Szuba MP, Amsterdam JD, Fernando AT 3rd, et al. 

Rapid antidepressant response after nocturnal TRH administration in patients with bipolar type I and bipolar type II major depression

 [published correction appears in J Clin Psychopharmacol. 2005 Dec;25(6):538. Fernando, Antonio T 3rd [added]; Gary, Keith A [added]; Whybrow, Peter C [added]; Winokur, Andrew [added]]. 

3. Bottlender R, Rudolf D, Strauss A, Möller HJ. 

Are low basal serum levels of the thyroid stimulating hormone (b-TSH) a risk factor for switches into states of expansive syndromes (known in Germany as "maniform syndromes" in bipolar I depression? 

4. Cole DP, Thase ME, Mallinger AG, et al. 

Slower treatment response in bipolar depression predicted by lower pretreatment thyroid function

Comparison of thyroid function in different emotional states of drug-naïve patients with bipolar disorder

Do your patients have abnormal thyroid indices? Researchers performed a comparison of thyroid function based on mood state in drug-naïve patients with bipolar disorder.

Thyroid Function in Drug-Naïve Bipolar Disorder

“Mr Jerry” is a 52-year-old Caucasian male with a 25-year history of bipolar I disorder, whose most recent episode involved depression with psychotic features. Eighteen months ago, he had surgery to repair a detached retina (non-traumatic) after noticing an acute worsening of vision in his right eye over a 1-week period. Six months later, he was in a motor vehicle accident that resulted in a traumatic macular hole in the same eye that required surgical repair. He also has persistent corneal edema of his right eye. He is not a candidate for further surgery, given overall poor visual potential. His visual impairments are a contributing factor to his depression. As he is outpatient psychiatric, how would you address his concerns?

The brain and the retina develop from the same neuroectodermal tissue.

 As a result, retinal pathology may parallel changes in the brain.

 A recent study of patients with bipolar disorder found abnormalities in retinal arterioles and venules.

 One case-control study investigated ocular disease in bipolar disorder, finding an association with glaucoma, but not retinal disease.

 However, the incidence of retinal disease in bipolar disorder has not been investigated in a longitudinal cohort study.

 investigated the association between retinal disease and bipolar disorder in a nationwide cohort study. They utilized the Taiwan National (Longitudinal) Health Insurance Database. The authors included patients aged 12 years and older with ICD-9 bipolar disorder confirmed by board-certified psychiatrists at least twice between 2001 and 2009. Cohort members had no history of retinal diseases before enrollment. Patients with bipolar disorder were matched 1:4 with controls (who had no history of ICD-9 mood or psychotic disorders) based on age, sex, residence, income, and comorbidities (medical and ophthalmological).

The primary outcomes were 5 non-degenerative retinal diseases: retinal detachment, primary retinopathy, diabetic retinopathy, hypertensive retinopathy, and retinal vascular complications. The risk of retinal disease was estimated using conditional Cox regression analyses, adjusting for the aforementioned covariates, as well as psychotropic medications.

The cohort consisted of 73,271 patients with bipolar disorder and 293,084 controls. The mean subject age was 38, 44% were male, and the mean follow-up duration was 6.7 years. Patients with bipolar disorder had a significantly higher incidence rate of any retinal disease versus controls (1.3% versus 0.5%), as well as each of the 5 individual retinal diseases. The mean age at diagnosis of any retinal disease was almost 3 years earlier in patients with bipolar disorder. 

After controlling for covariates, patients with bipolar disorder were 2.4 times more likely to develop retinal disease than controls (HR=2.43, 95% CI 2.14-2.75). The HRs for individual retinal diseases ranged from 2.26 to 3.46. The magnitude of cumulative exposure to psychotropic medications was not associated with the development of any retinal disease in patients with bipolar disorder.

The authors concluded that patients with bipolar disorder had a higher risk of retinal detachment, retinopathy, and retinal vascular complications, after controlling for covariates. Patients with bipolar disorder were diagnosed with retinal disease at a younger age than the well-matched controls. Psychotropic medications used in the treatment of bipolar disorder were not associated with the incidence of retinal disease.

The primary study strength was the use of a population-based cohort with linkage to national data registers. The selection of hospitalized patients provides a reasonable indicator of illness severity. Study limitations included the exclusion of diabetic and hypertensive retinopathy as well as degenerative retinal diseases, which could lead to underestimation of the risk of retinal disease; that data on medications cannot account for potential nonadherence; and that many retinal problems can be mostly symptomatic until advanced stages.

This study demonstrates that patients with bipolar disorder have an increased incidence of non-degenerative retinal disease, independent of psychotropic medications. Psychiatrists should be aware of ocular disease risks in this patient population.

The retina as a window to the brain-from eye research to CNS disorders

3. Appaji A, Nagendra B, Chako DM, et al. 

Retinal vascular abnormalities in schizophrenia and bipolar disorder: a window to the brain

Association of ocular diseases with schizophrenia, bipolar disorder, and major depressive disorder: a retrospective case-control, population-based study

Risk of retinal disease in patients with bipolar disorder: a nationwide cohort study

The eyes are a window to the brain. Researchers performed a nationwide cohort study of the risk of retinal disease in patients with bipolar disorder.

Retinal Disease in Patients With Bipolar Disorder

“Mr Samuel” is a 48-year-old Caucasian male with a 25-year history of bipolar I disorder with psychotic features and post-traumatic stress disorder (PTSD) who is seen for monthly outpatient visits. He has been clinically stable with no psychiatric hospitalizations in the past 15 years on a regimen of quetiapine 500 mg daily and valproic acid 750 mg daily. He has comorbid hypertension, for which he previously took valsartan and is currently taking lisinopril. He also has dyslipidemia, likely a familial hypertriglyceridemia, with a recent fasting total cholesterol of 244 mg/dL and triglycerides of 384 mg/dL, for which he was started on simvastatin. His fasting glucose is normal at 86 mg/dL. His body mass index has been stable at 26 for the past year.

Bipolar disorder is associated with increased cardiovascular disease morbidity and mortality.

 However, there is not a corresponding increase in cardiovascular disease in the first-degree relatives of patients with bipolar disorder, suggesting a key role for factors inherent to the disorder and its treatment.

 Obesity (both general and abdominal) and impaired glucose metabolism (including impaired fasting glucose and frank diabetes) are major risk factors for cardiovascular disease.

 conducted a systematic review and meta-analysis of the pooled prevalence of type 2 diabetes mellitus, impaired fasting glucose, and general and abdominal obesity in patients with bipolar disorder. The authors systematically searched Embase, Medline, PubMed, and APA PsycArticles from inception through June 2021. They included 1) cross-sectional, retrospective, and prospective studies in English or Chinese; 2) studies that diagnosed bipolar disorder by DSM or ICD criteria; and 3) studies that used valid criteria to measure fasting glucose. Studies that were not peer-reviewed, did not quantitatively measure glucose or obesity, or only included children and adolescents were excluded. Data were analyzed using random-effects meta-analysis. The authors also used meta-regression analyses to assess the effects of the following covariates: age, sex, BMI, study design, and illness duration. Article quality was assessed using the Newcastle-Ottawa Scale.

The authors identified 6352 studies, of which 49 were included in the meta-analysis, including 32 cross-sectional, 15 retrospective, and 1 prospective study. Twenty-three studies recruited age- and sex-matched controls, and 23 studies met the criterion for satisfactory methodological quality. The pooled prevalence of type 2 diabetes in 23 studies (n=342,826) was 9.6% (95% CI 7.3-12.2%) and was moderated by older age and female sex. The pooled prevalence of impaired fasting glucose (ADA criteria of ≥100 mg/dL) in 21 studies (n=2454) was 22.4% (95% CI 16.7-28.7%), with no significant moderators. The pooled prevalence of impaired fasting glucose (WHO criteria of ≥110 mg/dL) in 11 studies (n=1582) was 14.8% (95% CI 10.8-19.3%) and was moderated by study design (higher prevalence in retrospective studies).

The pooled prevalence of obesity in 32 studies (n=322,494) was 29% (95% CI 22.8-35.6%), with no significant moderators. The pooled prevalence of abdominal obesity in 16 studies (n=2378) was 51.1% (95% CI 45.0-57.3%, and was moderated by longer illness duration and female sex. In 7 studies with controls, there was a 1.6-fold increased risk of diabetes in patients with bipolar disorder. In 11 studies with controls, there was a significant 1.7-fold increased risk of obesity in patients with bipolar disorder.

The authors found a 10% prevalence of type 2 diabetes, an approximate 20% prevalence of impaired glucose tolerance, an almost 30% prevalence of obesity, and an over 50% prevalence of abdominal obesity in patients with bipolar disorder. Study strengths included the large sample size; consideration of impaired glucose tolerance and abdominal obesity separate from diabetes and general obesity; and the consideration of several potential moderators. A primary limitation was the lack of data on pharmacotherapies.

Bipolar disorder is associated with an increased prevalence of diabetes, impaired fasting glucose, and general and abdominal obesity. Primary prevention, screening, and treatment efforts are needed for this patient population to mitigate increased cardiovascular disease morbidity and mortality.

is a professor in the Department of Psychiatry and Health Behavior at Augusta University, Augusta, Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for 

1. Correll CU, Solmi M, Veronese N, et al. 

Prevalence, incidence and mortality from cardiovascular disease in patients with pooled and specific severe mental illness: a large-scale meta-analysis of 3,211,768 patients and 113,383,368 controls

 [published correction appears in World Psychiatry. 2018 Feb;17 (1):120]. 

2. Kessing LV, Ziersen SC, Andersen PK, Vinberg M. 

A nation-wide population-based longitudinal study mapping physical diseases in patients with bipolar disorder and their siblings

Prevalence of type 2 diabetes mellitus, impaired fasting glucose, general obesity, and abdominal obesity in patients with bipolar disorder: a systematic review and meta-analysis

Researchers performed a meta-analysis of the prevalence of type 2 diabetes, impaired fasting, glucose, and general and abdominal obesity in bipolar disorder.

Glucose Metabolism and Obesity in Bipolar Disorder

The key takeaways from the roundtable discussion we had that stood out to me after hearing from colleagues is that there is still a fair amount of use of the older medicines out there like lithium. Part of the problem is, however, when we take a look at agents with a low therapeutic index. There is the possibility of no benefit depending on too low a level, or the possibility of serious life-threatening issues with too high a dose; thus the need for monitoring. There is also a need to consider issues based on thyroid function and renal function aside from the litany of thins, including dermatological and central nervous system issues associated with this basic elemental solve.

The use of anticonvulsants also came up. In individuals that may be “self-medicating” with alcohol, some agents like depakote might be more useful in individuals with underlying hostility or explosiveness aimed at potentially harming others. Agents like carbamazepine or divalproex might be useful agents. There was discussion about lamotrigine, but that is a medicine that is also FDA approved for bipolar depressive maintenance. There are several studies where it did not show solid efficacy; additionally, you have to titrate up very gradually to avert the likelihood of Stevens-Johnson syndrome. The possibility of these additional factors might become problematic for individuals, keeping it mind that it certainly could be something useful.

The utilization of atypical antipsychotics has now garnered a bit more attention; certainly, the advent of Seroquel XR (quetiapine) helped lead a charge of taking a look at the malleability associated with atypical antipsychotics prior to that olanzapine combined with fluoxetine would certainly be a consideration. Trying to keep things as simple as possible can be a challenge when mixing in additional medicine. That is where single agents may be worthwhile. With Seroquel XR, unfortunately, 1 out of 2 people feel very sleepy, 1 out of 3 have severe dry mouth. Sometimes, finding the right dose can be difficult. That is where the dosing becomes a little bit trickier. It is a medicine given with food and can give a severe hungover feeling in individuals later on; that is where clinicians may feel reticent.

Latuda (lurasidone) has a decent track record. Unlike Seroquel XR, it should be given with food for it to work well. Otherwise, you only get half the benefit. And then the question is: what does will you need. And sometimes people may experience nausea and sedation associated with the use of the medicine, thereby limiting sometimes the possible full use of the agent. Vraylar (cariprazine) is a newer medicine that does not have the same track record a Latuda based on how long it has been available, but it certainly is one of the few medicines that has a broader spectrum of utilization, not just in the depressive episode but also the manic mixed episode state. That, to a degree, also brings a sense of comfort for clinicians, because Latuda is only approved for bipolar depression. Sometimes clinicians may feel gun-shy: might this medicine activate individuals and flip them over into a manic episode, and, if so, do we really have a sufficient amount of data associated with its use? Vraylar can be given once-daily it is not sedating, not activating, and it has a very long half-life, which means that sometimes people forget to take their medicine, that is ok. The flip side to that, though, side effects might linger for a week. It is a drug that has been well studied in doses even up to 3 times its highest dose. It is currently FDA recommended as not really compromise when it comes to cardiac status and has a placebo like effect on metabolics. It looks quite attractive for individuals where you don’t want gaining weight or having specific issues that might compromise metabolics. The other nice use of that particular medicine is that when patients show up with predominantly depressive symptoms, they will start out at the lowest dose and for the most part stay there. We certainly note that 1.5 mg but up to 3 mg will work there. If patients are having more mixed symptoms that is where the 3 mg dose might be better. If they are having more manic symptoms, that is where 4.5 mg or 6 mg might be a better fit.

Latest entrant in this game is Caplyta (lumateperone). It has a fixed dose of 42 mg and is only indicated for bipolar depression, but it is indicated for bipolar type 1 and type 2, which is interesting because only Seroquel XR and Caplyta have been studied in bipolar 2 patients and you see benefit there. You also note a very clean metabolic profile associated with the medicine. Part of the discussion with the colleagues was taking a look at all of the different options we have, keeping in mind that lithium is the only medication we have that averts suicidality in bipolar disorder. Sometimes patients don’t just respond to one medicine. That is where additional data with other agents are useful.

The important thing is that when we take into consideration bipolar depression, this is a topic that on the surface looks simple but, in reality, can be complex but at the same time training individuals even in the primary care setting to take into consideration these options can help someone so that they are not necessarily lingering in a state in which they are experiencing different difficulties because of financial or interpersonal problem or even the likelihood of suicidality.

Wrapping it all up, there is a current sentiment that we have evolved to the point at which that although some individuals may be treatment refractory and require things including ECT or otherwise. Other modalities like repetitive transcranial magnetic stimulation, intranasal esketamine are not FDA approved in bipolar disorder. It resolves some discussion that ECT-intravenous ketamine might sometimes be useful for some individuals. But the important point is that we have additional tools in our psych-armamentarium and that readily help many individuals in the past that have been mired in suffering and might have experienced additional problems.

Causes like this represent to us the fact that moderate depressive symptoms are not always what they seem. We need to instruct our colleagues and counterparts about the differential associated with depressive symptomatology to take into consideration prior history, family history, and the comorbidity that the induvial experiences, also keeping in mind the aspirational note of what were trying to accomplish: above all, do no harm, and when presenting someone with options, make sure out option list is comprehensive and readily understood.

I appreciate the opportunity of taking part in this didactic experience and the fact that we continue to move down a path in which additional tools are set before us as clinicians. Thank you.

Gus Alva, MD, DFAPA, discusses key takeaways for the management of bipolar disorder.

Clinical Insights Regarding the Management of Bipolar Disorder

I think that this particular clinical history encapsulates some very fascinating points. Among these points might be what our first impression of this case might be, and what types of challenges a patient like this presents when they come into treatment. This is a young female patient of child-bearing age, who, upon speaking about her current symptomatology, one would immediately latch onto the concept that depressive symptoms are in play, as she has had several episodes that look like this. Upon further investigation, it turns out that there might be some mood oscillation in the background, which is a very important point, particularly in the primary care setting but also in the specialist setting. Our patients are not going to be the best historians; that means that sometimes we miss subtle points of import, such as periods of either mood oscillation, excessive activity, decreased need for sleep, irritability, and impulsivity. In the case of our patient, we certainly note that aside from depressive episodes she has had, she has certainly had some mood oscillatory issues that we need to keep in mind.

Some of the red flags to keep in mind include different factors, such as lingering vegetative symptoms. She has been fine with treatment that might actually work for most individuals. She has been exposed to an SSRI agent that has been ramped up sufficiently. We note, however, that as dose was being ramped up, a bit of activation occurred. Sometimes, the thought in mind should be: Are we potentially evoking medication that doesn’t work for our patient as opposed to actually reconsidering the possibility that in our differential of major depressive order that bipolar disorder may not have been captured previously. We know that family history is strongly burdened by the possibility of mood oscillatory states, and this would be indicative of problem. We know that her age and medical comorbidities are of great import. We obviously want to make sure that someone who is already weighing a little extra is not exposed to agents that might pack on more weight, and, as a consequence of that compromise, the possibility of continued use of medications that otherwise would be highly advantageous. We know that when someone walks into clinical setting and say they have been depressed the past 2 weeks, are experiencing vegetative symptoms that are impacting their day-to-day life and interactions with others, we don’t always jump to the conclusion of unipolar depression. DSM-5 stipulates that differential diagnosis of bipolar disorder of depressive episode be kept in mind. Our case her illustrates those very points.

You’ll note that initially she was managed with psychotherapy but then, subsequently, the thought was, are we barking up the wrong tree? Should we seek out some specialty care that was done in appropriate manner. In the past, we would have thought that different types of mood stabilizing medications, which typically would be a but more useful in individual who are experiencing a bit more manic or mixed symptomatology. Sometimes we don’t capture the essence of countering specific problems with an agent that might actually have a profile that is attractive for an individual like our patient.

In the primary care setting, when someone sees a PHQ9 of 18 that designates severe depression. But we now see couched behind that the mood disorder questionnaire as a way of propelling additional dialogue about the possibility of bipolar disorder based on current depressive symptoms the patient is experiences. Obviously, an SSRI would not be the indicated agent to utilize in this patient at this particular juncture, because she has been experiencing more depressive symptoms that are tied in with bipolar disorder. In this case, a mood stabilizer that could have a nice impact on lifting depressive symptoms would probably be of greater benefit, keeping in mind the weight related issues and the fact that she is already diabetic and we don’t want to aggravative underlying metabolic issues. There are also other agents that might actually help out in stabilizing mood, particularly when someone is experiencing a depressive episode. We know that within the family of the antipsychotics would be agents that would address symptomatology that this patient is experiencing. But we want to keep in mind the overall ambulatory state of the individual. if someone is having problems with sleep, they will seek out an agent that helps with sleep but then subsequently might complain that they feel “out of it”; that is where agents that have a profile that is not necessarily evoking too much sedation might be useful. Sometimes, taking a medication with or without food could create an impediment for someone to actually comply with their utilization with the medicine and the dosing associated with the medicine would be of great import. Taking into context the overall profile of these medications based on the data available is also of great aid.

This case illustrated that if it walks, quacks, moves around like a duck, it might well be a chicken. In this case, it is well worth while reconsidering what our diagnosis is and consider the possibility of a mood disorder like bipolar disorder. We noted that at the very least she had had flares with her mood, where she did not need to sleep as much and felt more active and productive. Peering into those periods would be a great benefit for us in solidifying a diagnosis. Ultimately, when we try to get someone on the right trajectory. It is about getting the right questions in front of the person, to be able to unmask underlying issues that may have been in play. Although the lifetime problems for major depressive disorder are far greater than for bipolar disorder with depressive episodes, those of us who manage specialty settings often see individuals who bounce back between different clinicians and are now surprised that some people take 5 to 10 years before right diagnosis is made. This case readily illustrates multiple points that we need to keep in mind and helps solidify the approach that should be held with patients. There is no preset way of diagnosing individuals; our diagnosis can sometimes be fluid. That is why it is so important to look at family history and previous symptomatology, and maybe the possibility of individuals who have been misdiagnosed, having had psychiatric comorbidities that would be indicative of the likelihood of a condition like bipolar disorder.

Dr. Gus Alva shares his initial impressions on this case and treatment approaches to bipolar 1 disorder.

Clinical Impressions From the Patient Case

 Psychiatric Times presents this roundtable on the management of bipolar disorder, a phenomenal dialogue allowing clinicals a perspective regarding current trends and where we may be headed in the future.

This is an interesting case, as we take a look at this 23-year-old female who first comes in to see her psychiatrist with moderate depressive symptoms. At the time of the interview, her chief complaint included feeling like she’s lacking energy, she’s feeling depressed. She’s also reporting difficulty in paying attention, organizing her day, and accomplishing her tasks at work. Notably these symptoms started abruptly. Three weeks early, prior to that, she had been functioning better than usual, requiring very little sleep and getting more accomplished. Of significance, she reported two brief episodes of depression over the past 2 years. Each lasting about 2 months. And although the patient reported these depressive episodes as coming out of the blue, she learned after consulting with her therapist that they were related to significant psychosocial stress, stemming from the loss of her job and the deaths of 2 uncles, both of which were related to the COVID-19 pandemic. The patient reported that she still finds enjoyment talking to friends and socializing and she has hope of finding a new job and she’s constantly looking.

It’s noteworthy to bear in mind that in her first depressive episode she was treated with methylphenidate 25mg titrated up to 50 m and she stated feeling improved on this does with psychotherapy. Her second depressive episode, her does was bumped up to 100 mg which we saw improvement in depression, but she noted she felt a little activated and had trouble sleeping. With her third depressive episode, the therapist and PCP referred the patient over to a psychiatrist. Of great note should be her past psychological history: she was diagnosed with ADHD in middle school, during which time she responded well to methylphenidate. She continued to do well until her college years at which time she began experiencing difficulty falling asleep as well as irritability. At that time, she discontinued methylphenidate and was psychiatric drug free. She found that practicing mindfulness and yoga on a daily basis helped her residual ADHD symptoms. Of note, she had no history of suicidal thoughts or behavior, self-injurious behaviors, psychiatric hospitalization, or problems with substance abuse. Of note, regarding medical comorbidities, she was diagnosed a year earlier with type 2 diabetes, which was managed with metformin 1000 mg twice daily and her hemoglobin A1C was not poorly controlled. She was also diagnosed with high blood pressure 2 years earlier, that is managed by lisinopril 20 mg once daily. We noted that her BMI is 31, which is indicative of obesity. All other lab values were within normal limit. Significantly, her TSH was in the normal range and her urine toxicology screening was negative. Upon further querying of her family history, her maternal grandmother was diagnosed with a nervous breakdown and spent 2 months in a psychiatric hospital in her 30s. Her mother required little sleep, had a history of impulsive spending, and had a history of starting projects that she didn’t finish. The patient’s paternal uncles had a history of depression as well as alcohol abuse. Upon doing assessments, her PHQ9 is indicative of 18 points and her mood questionnaire she scored an 8.

Gus Alva, MD, DFAPA, presents the case of a 23-year-old female diagnosed with bipolar 1 disorder.

Case Presentation: A 23-Year-Old With Bipolar Disorder

 (BD) affects 1% to 3% of the world’s population and is characterized by alterations in mood, levels of energy, and functioning. Despite these common features, BD includes a group of polymorphic and heterogeneous conditions in terms of clinical presentation, course, response to treatment, and functional outcome.

 Several sociodemographic and clinical variables have been investigated as potential factors influencing the development and course of illness, such as age at onset, employment status, marital status, number of manic/depressive episodes, predominant polarity, and—above all—gender and sex.

There has been a rising interest in gender-related specificities in BD (

However, the presence of clinical and epidemiological distinctions between male and female patients and their role in the diagnostic and therapeutic process is still controversial.

 Sex specificity may affect many variables, including incidence, prevalence, subtypes (BD I and BD II), rapid cycling, suicidal behavior, comorbidities, treatment response, and adverse effects. Moreover, among females, hormonal oscillations related to the menstrual and reproductive cycle may influence the disease and its treatment.

Compelling evidence has documented an almost equal male-female sex ratio in incidence and lifetime BD prevalence rates (

Nonetheless, recent studies suggest an increased frequency of BD diagnosis among women, for both BD I and BD II. Furthermore, hypomania, and consequently BD II subtype, are more frequently associated with female sex.

Although age at first mood episode does not apparently differ between women and men, men more commonly experience a first manic episode during childhood.

 Men more often have a first manic episode, whereas women seem more likely to face a depressive one.

 In addition, being female is more frequently related to depressive recurrences, depressive predominant polarity, and higher lifetime prevalence of psychotic depression.

Women more often report depression and large fluctuations in mood as well as more frequent mood oscillations across the menstrual cycle.

 On this basis, the identification of BD in women may be more challenging, leading to a higher rate of misdiagnosis of major depressive disorder. Indeed, some other characteristics may help clinicians in the successful recognition of BD in women, including lifetime rapid cycling

 The probability of mixed symptoms in females increases consistently with the severity of hypomania but decreases at the most severe levels of hypomania.

Suicide attempt rates have been significantly more frequent among females, even though death by suicide has occurred more commonly in men.

 As a result, physicians should consider the possibility of an unrecognized bipolar diathesis if they see frequent depressive recurrences despite antidepressant therapy, the presence of psychotic features during a depressive episode, and a high number of suicide attempts in women.

Psychiatric and medical comorbidities often negatively affect BD course, regardless of sex. Comorbidity with alcohol and other substance use disorders (eg, cannabis abuse/dependence and pathological gambling) has been more frequently documented among males.

 However, Goodwin and Jamison have suggested a higher prevalence of alcohol abuse among women with BD II.

 Co-occurrence of personality disorders (particularly of cluster B), eating disorders such as bulimia, and posttraumatic stress disorder was generally observed with a higher frequency among females.

 A sex-specific effect has also been illustrated for comorbid obsessive-compulsive disorder (OCD) and anxiety spectrum disorders, with increased OCD rates in males and panic disorder in females. Organic conditions such as migraine, thyroid disorders (especially hypothyroidism), and autoimmune disorders seem to be more commonly associated with female gender in BD.

Previous investigation of sex differences in the most affected domains in BD—including executive function, verbal and visual memory, verbal learning, attention and processing speed—did not identify differing results. However, recent findings showed a better performance in working memory tasks among males, whereas a better performance was found in verbal learning and memory recognition tasks among females.

 Finally, a sex differential emerged in psychosocial functioning, with females with BD tending to report better social and occupational status than their male counterparts.

The correlation between sex/gender and response to pharmacological treatment has been extensively investigated, with a particular focus on mood stabilizers and antipsychotics. Beyond an increased use of antidepressants, women with BD seem to more frequently receive a combination treatment, whereas men have more often reported receiving lithium.

 Considering sex differences in clinical response to lithium, a pooled data analysis outlined response rates of 65.6% in women and 61.0% in men. Another longitudinal study found that, in comparison with men treated with lithium, women treated with lithium had a significantly longer median time to first recurrence.

The use of antipsychotics in BD has increased in past decades, apparently with no differences in their prescription.

 Regarding efficacy, in an 8-week trial of treatment with placebo, olanzapine, or olanzapine/fluoxetine in combination, male patients with depression and manic-predominant polarity experienced higher rates of improvement compared with those with depressive polarity. Among females, no differences in terms of response were observed by means of predominant polarity.

Some authors have hypothesized a correlation between sex and occurrence, intensity, and type of medication adverse effects, thus influencing their prescribing patterns. Regarding lithium, female sex emerged as the main risk factor for the development of hypothyroidism during treatment, especially for women aged 40 to 59 years. Valproate use in females may lead to polycystic ovaries, polycystic ovary syndrome, hyperandrogenism, and obesity. Valproate needs to have an extremely low priority in women of childbearing potential due to the important risks of neurodevelopmental delays and polycystic ovary. However, it can be effective and well tolerated in females not of reproductive potential. Moreover, many typical and some atypical antipsychotics may be associated with hyperprolactinemia, which can result in galactorrhea, amenorrhea, and other menstrual cycle irregularities.

 Although females with BD were generally more adherent to therapeutic indications, they nonetheless seemed to be more concerned about adverse effects like weight gain.

In terms of nonpharmacological strategies, female patients with depression underwent significantly fewer antidepressant drug trials than their male counterparts before being prescribed electroconvulsive therapy. When used in patients with schizophrenia, its effectiveness was greater in females, but this difference was not replicated in individuals with BD, possibly because of the small sample size.

 No evidence supported the notion of a different response to psychotherapy between genders.

Women physiologically experience endogenous fluctuations in ovarian hormone levels, including recurring oscillation of estradiol and progesterone. These fluctuations may affect BD pathophysiology and clinical presentation. It is worth noting that symptoms may worsen when gonadal hormone levels are low, either during the premenstrual phase of the cycle—thus hindering the distinction from premenstrual dysphoric disorder4—and postpartum.

 This period may be burdened by a relevant risk of BD onset and relapse. For instance, a recent meta-analysis found an overall postpartum relapse risk of 37%, with almost a quarter of those suffering from affective psychosis, mania, mixed episodes, or relapses requiring hospitalization, and the remaining patients suffering from nonpsychotic affective episodes, mostly depressive.

 Accordingly, clinical trials suggested that exogenous estrogenic treatments may improve specific symptoms of BD.

During pregnancy, women with BD should undergo close monitoring because of the correlation between BD and pregnancy complications, as well as potential congenital anomalies in infants. The discontinuation of medications may trigger a mood recurrence and thus lead to disruption of daily living functioning, including a patient’s ability to take care of the child.

 By contrast, the teratogenic potential of various mood stabilizers must be kept in mind; lithium may enhance the risk of cardiovascular malformations (such as Ebstein anomaly), and valproate and carbamazepine are both associated with the risk of neural tube defects, including spina bifida. Hence, when treating women with BD who wish to become pregnant, the risk-benefit ratio should be assessed by evaluating the teratogenic risk of pharmacotherapy and the negative impact of untreated BD symptoms on the pregnant woman and the fetus.

The same shrewdness should be promoted in treating women with BD during breastfeeding. Some mood stabilizers, including carbamazepine and valproate, are not contraindicated, whereas lithium is not compatible with lactation. In addition, there is no consensus regarding the use of antipsychotics during pregnancy and breastfeeding.

Finally, during the menopause transition, many women face unspecific mood symptoms. In females with BD, the perimenopausal phase may enhance mood instability, with increased depressive symptoms and reduced manic symptoms.

Some epidemiological and clinical characteristics of BD may differ between the sexes. Although further investigation is encouraged, the preceding preliminary findings may guide practitioners in clinical practice by facilitating BD identification, especially in case of depressive onset, and by orienting treatment interventions, with a special focus on life events related to the female reproductive cycle. The effort should go towards avoiding valproate and carbamazepine in women of child-bearing potential, unless associated with hormonal contraceptives.

is an associate professor of psychiatry at the University of Milan, and director of the psychiatric clinic of the Ospedale Luigi Sacco-Polo Universitario of Milan. He is also a scientific advisor in the Department of Psychiatry and Behavioral Sciences of Stanford University and cochair of the International College of Obsessive Compulsive Spectrum Disorders. 

is a psychiatrist in the Department of Psychiatry, University of Milan. 

 is a resident in psychiatry in the Department of Biomedical and Clinical Sciences of the University of Milan. 

In the last 3 years, Dr Dell’Osso has received lecture honoraria and research grants from Angelini, Lundbeck, Janssen, Pfizer, Otzuka, Neuraxpharm, and Livanova. The other authors have no conflicts to declare.

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Gender and Sex Issues in Bipolar Disorder

Treatment-resistant bipolar depression (TRBD) is defined by non-remission after 2 8-week trials of recommended medications, including combination therapy, at therapeutic doses, and associated with increased psychiatric hospitalizations and disability, and poorer quality of life.

 The prevalence of type 2 diabetes and insulin resistance in patients with bipolar disorder is approximately 22% and 32%, respectively, and these conditions may worsen illness course.

“Mr Joseph” is a 60-year-old Caucasian male with a history of chronic bipolar I disorder, whose most recent episode included depression without psychotic features. He failed a previous trial of lithium due to adverse effects on renal function. He had improved mood with treatment with ziprasidone, titrated to 40 mg qAM and 80 mg qPM, although he has residual depressive symptoms. He gained weight with ziprasidone, with an increase in BMI from 28 to 32. He maintained a normal fasting glucose. He requested to continue ziprasidone, and 3 months ago was started on metformin, which was titrated to 1000 mg BID. At his most recent outpatient clinic visit, his BMI had decreased to 29.5, and he also noted mild improvements in mood and anxiety.

Calkin and colleagues hypothesized that patients with TRBD who met criteria for insulin resistance would exhibit a favorable response to metformin, which has insulin-sensitizing properties.

 They performed a randomized quadruple-masked (patient, investigator, outcomes assessor, statistician) trial of adjunctive metformin at 2 sites in Canada and the United States. They included adults aged 18 and older with DSM-5 bipolar disorder and unremitting depressive symptoms (Montgomery-Asberg Depression Rating Score [MADRS] score ≥15) for at least 4 weeks despite optimal treatment.

Subjects were screened for insulin resistance using the Homeostatic Model Assessment-Insulin Resistance (HOMA-IR) equation, which is based on fasting blood glucose and insulin. Subjects were excluded if they did not have insulin resistance (HOMA-IR <1.8), had manic symptoms (Young Mania Rating Scale score ≥15), had a suicidal ideation rating of 5 on the Columbia Suicide Severity Rating Scale, were already receiving or were allergic to metformin, or had liver function tests ≥3 times the upper limit of normal.

Subjects received metformin 500 mg (or placebo) twice daily for 1 week, then titrated to 1000 mg BID for up to 25 additional weeks. The minimum maintenance dose of metformin was 1500 mg daily. The MADRS was administered, and insulin resistance was measured at baseline, week 2, and every 4 weeks thereafter (primary outcomes). Secondary outcomes included the Clinical Global Impressions Scale (bipolar disorders version; CGI-BP) and the Global Assessment of Functioning (GAF) scale. Returned pill counts were used to determine study medication adherence. The primary hypothesis that metformin would reverse insulin resistance (conversion) was tested using Fisher’s exact test. Improvements in MADRS scores (and other outcomes) in converters were tested using mixed-effects linear models.

The authors consented and screened 88 subjects, of whom 50 were randomized. Efficacy and safety data were reported for 45 subjects (20 metformin and 25 placebo). Thirty-nine subjects (87%) completed the study to the week-14 primary outcome endpoint, and 28 subjects completed the full 26 weeks. Medication adherence was 97% in both treatment groups. Mean subject age was 48, 76% were women, and the mean illness duration was 26 years. There were no significant between-group differences in weight, BMI, glucose, insulin, or blood levels of lithium or lamotrigine.

Ten metformin-treated patients no longer met insulin resistance criteria (converters) at week 14, versus 1 placebo-treated patient (Fisher’s exact p=0.0009). Converters had a significantly greater reduction in MADRS total scores beginning at week 6 and continuing through week 26, with large effect sizes (1.04 to 1.17). There were concordant improvements in GAF, Hamilton anxiety scale, and, to a lesser extent, CGI-BP scores in converters. The most common adverse events were diarrhea and vomiting, which were expected in the metformin group. At week 14, metformin-treated patients lost 1.7 kg and placebo-treated patients gained 1.4 kg, and this difference was statistically significant.

The authors concluded that reversal of insulin resistance by metformin resulted in statistically and clinically significant sustained improvements in depression, with no changes in mania, in patients with TRBD. No serious adverse events occurred, and the most common adverse events were gastrointestinal symptoms. Study limitations included the modest sample size, and whether a higher rate of conversion from insulin resistance could be achieved with either higher doses or extended-release preparations of metformin.

Reversal of insulin resistance by metformin improves depression, anxiety, and general functioning in a large proportion of patients with TRBD. These findings warrant replication in a larger trial.

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Metformin in Treatment-Resistant Bipolar Depression

frequently receive polypharmacy, with up to 20% of patients getting 4 or more bipolar medications.

 Problematic drug-drug interactions occur often, impacting effectiveness or safety. They can be pharmacokinetic or pharmacodynamic. Yet these interactions receive little attention in the various practice guidelines and algorithms for the psychopharmacologic management of bipolar disorder. Some of these will be summarized here and in a subsequent article.

Up to 20% of patients with bipolar disorder have 4 or more medications, so it is important to be aware of these common drug-drug interactions.

Bipolar Disorder