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Many patients with bipolar disorder (BD) have comorbid substance use disorders, including nicotine use. Some 

the chances of successfully addressing other substance use.

The mechanisms of nicotine and other substances are similar, so it is necessary to stop all substances that are maintaining the pathological processes. Patients, and some clinicians, erroneously believe it is OK to wait to address cigarette and other nicotine use.

The most effective smoking cessation medication is 

. The EAGLES study, a randomized, double-blind, placebo-controlled trial (N=8144) compared varenicline, bupropion, and nicotine replacement therapy (NRT). The results confirmed many smaller 

 that varenicline treatment had the best outcome (defined as abstinence at weeks 9-12).

 The investigators also studied the effects among various diagnoses by dividing patients into 2 equal cohorts—one with and the other without psychiatric disorders (70% unipolar and bipolar mood disorders, 20% anxiety disorders, and 10% psychotic disorders). The study found varenicline performed the best of the 4 treatments in both groups. In the nonpsychiatric cohort, abstinence rates were 38% for varenicline vs 26% on other active treatments and 14% on placebo. In the psychiatric cohort, abstinence occurred in 29% on varenicline, 19% to 20% on the other medications, and 11% on placebo.

The safety results may surprise some clinicians and patients. No differences were reported in moderate to severe neuropsychiatric adverse effects (eg, depression, suicidality, aggression) between varenicline and placebo in either cohort. In fact, as a result of the EAGLES findings, the US Food and Drug Administration removed the longstanding black box warning regarding such adverse effects. Interestingly, these neuropsychiatric adverse events can occur, but they are not more common if the patient is on varenicline. The effects are proposed to be due to 

 withdrawal. These safety results are consistent with many other studies, and the call to “stop ringing the alarm bell” was in the 

 Previous studies included patients with stabilized BD, and findings showed excellent efficacy and safety regarding precipitation of mood swings. There seem to be no significant drug interactions with any bipolar medications.

If smoking cessation fails on varenicline, controlled studies have shown augmentations with NRT or bupropion can add efficacy.

 Bupropion, however, is probably not a good choice for a patient with BD. The preferred augmentation would be NRT with patch and oral agents followed by slow taper; this strategy may blunt the nicotine withdrawal and increase success rates.

One minor adverse effect of varenicline is insomnia. 

 and disturbed awakenings associated with posttraumatic stress disorder (PTSD) may increase with varenicline. Before initiating varenicline, sleep disturbance associated with PTSD should be managed with prazosin. Five out of 8 placebo-controlled studies have found efficacy for prazosin. (Prazosin for PTSD in BD will be discussed in a future article; dosing and procedures with prazosin are best exemplified by Raskind et al.

 Prazosin may need to be increased if the nightmares resume or increase after starting varenicline.)

The hydrocarbons in cigarette smoke increase the activity of cytochrome P450 1A2, which metabolizes olanzapine and clozapine. Smoking cessation will, therefore, result in gradual deinduction of this enzyme, and plasma levels of these antipsychotics will increase over a week or 2.

is associate professor of psychiatry at Harvard Medical School and colead psychiatrist at the US Department of Veterans Affairs, National Telemental Health Center, Bipolar Disorders Telehealth Program, Brockton, Massachusetts.

A review of smoking cessation in bipolar disorder: implications for future research

A molecular basis for nicotine as a gateway drug.

3. Leão RM, Cruz FC, Vendruscolo LF, et al. 

Chronic nicotine activates stress/reward-related brain regions and facilitates the transition to compulsive alcohol drinking.

4. Anthenelli RM, Benowitz NL, West R, et al. 

Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomised, placebo-controlled clinical trial

6. Rose JE, Behm FM. Combination treatment with varenicline and bupropion in an adaptive smoking cessation paradigm. 

7. Koegelenberg CF, Noor F, Bateman ED, et al. Efficacy of varenicline combined with nicotine replacement therapy vs varenicline alone for smoking cessation: a randomized clinical trial. 

8. Raskind MA, Peterson K, Williams T, et al. A trial of prazosin for combat trauma PTSD with nightmares in active-duty soldiers returned from Iraq and Afghanistan. 

Many patients with bipolar and other psychiatric disorders believe it is better to wait to address cigarette and other nicotine use. Here is why that is not necessarily the case.

Addressing Smoking: Is Varenicline the Answer?

In what 5 ways can anxiety present in bipolar disorder? 

5 Types of Anxious Bipolar Disorder 

A manic episode is a psychiatric condition characterized by the presence of elevated, expansive, or irritable mood; grandiosity; increased goal-directed activity; risk-taking behaviors; pressured speech; decreased need for sleep; racing thoughts; and distractibility. Most commonly, manic episodes occur because of an underlying primary bipolar disorder. However, manic episodes can occur as a result of multiple other causes, including general medical conditions, substance abuse, and medication side effects. One medication that has been hypothesized to precipitate manic episodes is the chemotherapy agent methotrexate.

Methotrexate is used in the treatment of multiple forms of 

 through folate antagonism; it is also used to treat multiple autoimmune conditions.

 Although there is very limited literature describing an association between methotrexate and the occurrence of manic episodes, there have been reported cases of manic episodes in patients with stable bipolar disorder following the administration of methotrexate.

 To date, however, there have been no reported cases of manic episodes precipitated by methotrexate in patients without an existing diagnosis of bipolar disorder.

This case report demonstrates the acute onset of mania in a patient with no history of 

, which putatively was precipitated by the use of intrathecal methotrexate in the treatment of acute lymphoblastic leukemia.

“Charlie” is an adolescent patient with a prior psychiatric history of attention-deficit/hyperactivity disorder (ADHD) and a medical history of acute lymphocytic leukemia (ALL). He had no prior history of affective or psychotic disorders. Family history was significant for depression in a maternal aunt, but there was no family history of bipolar disorder or psychosis. After the patient was diagnosed with high-risk ALL, he was started on induction chemotherapy. He completed a course of prednisone treatment and received a second dose of intrathecal methotrexate (IT MTX) a few days prior to presentation.

At that time, Charlie presented to the hospital with several days history of altered mental status in the form of irritability, elevated mood, poor sleep, pressured speech, grandiosity, 

Upon admission, computed tomography (CT) head without contrast, magnetic resonance imaging (MRI) brain with and without contrast, magnetic resonance angiography (MRA) head without contrast, and magnetic resonance venography (MRV) head with and without contrast were all unremarkable. Awake electroencephalogram (EEG) was normal. Labs including anti- hyroperoxidase (TPO), thyroid peroxidase antibody, paraneoplastic antibody panel, autoimmune encephalopathy panel, and N-methyl-D-aspartate (NMDA) receptor antibody (CSF and serum) were negative. Ammonia, ceruloplasmin, Vitamin B12, TSH, and T4 were normal.

After being evaluated by the psychiatric consult liaison (C-L) team, Charlie was started on olanzapine, which was titrated to 10 mg BID for treatment of acute manic and psychotic symptoms. During the following days, Charlie remained disorganized and delusional, so olanzapine was changed to haloperidol 1 mg BID. The next few days he was reported to be doing marginally better, with improved 

 and less pressured speech, though remained somewhat disorganized and delusional.

On day 9 of admission, Charlie received third IT MTX treatment. On the following day, he was very restless, making bizarre hand movements, pacing around the room, with pressured speech and tangential thoughts, and remained hyper-religious with delusions of grandeur. Following reassessment by the C-L team, he was started on sodium valproate and quetiapine in addition to haloperidol 1 mg BID. Total daily doses of sodium valproate and quetiapine were gradually titrated up to 1250 mg and 350 mg, respectively. Charlie could not tolerate further increases in quetiapine beyond 350 mg daily due to excessive sedation, and haloperidol was discontinued due to prolonged QTc. Lorazepam 1 mg TID was added for management of agitation and irritability.

During the following days, Charlie’s sleep started to improve with periods of lucid thoughts. He gradually became much calmer and redirectable, although remained occasionally delusional. As his mental status started to improve, quetiapine was decreased to 300 mg daily and lorazepam was decreased to 0.5 mg in the evening. Sodium valproate was continued at 1250 mg daily.

On day 16, Charlie received a fourth scheduled IT MTX treatment, with deterioration of mental status by the following day. He was noted to have more disorganized speech and delusional thoughts. Quetiapine was gradually titrated to 700 mg daily while sodium valproate was kept at 1250 mg daily.

Charlie showed marked improvement in mental status over the next few days of treatment, with less pressured speech and less disorganization. He continued to have tangential and racing thoughts but with much less intensity. Following stabilization, Charlie was discharged to home on a medication regimen that consisted of sodium valproate 1250 mg daily, quetiapine 700 mg daily, and lorazepam 0.5 mg TID.

After discharge, Charlie was followed by the psychiatric C-L team during outpatient visits to the Hem/Onc clinic. Five days after discharge, his thought process and behavior were noted to be much more organized. He continued to have some delusional thinking but was able to interact and engage in daily activities. Due to complaints of tiredness and increased sleep during the daytime, quetiapine was decreased to 500 mg daily and lorazepam was discontinued. Sodium valproate was continued at 1250 mg daily.

Twelve days following discharge, Charlie received fifth and last IT MTX treatment as scheduled. Six days after that, he was readmitted with acute manic and psychotic symptoms similar to the first admission. Following evaluation by psychiatry, Charlie was continued on sodium valproate 1250 mg daily, and quetiapine was increased to 600 mg daily. Due to elevated valproic acid (113.4 ug/mL, ref range 50-100 mcg/mL) and ammonia (97 umol/ L, ref range 11-32 umol/ L) levels, sodium valproate was subsequently decreased to 750 mg daily. During the following days, his behavior and mental status started to improve. After 6 days of hospitalization, the patient was discharged home on quetiapine 600 mg daily and sodium valproate 750 mg daily.

Seven days later, the patient presented at the outpatient clinic with markedly improved mental status and overall functioning. Sodium valproate 750 mg daily and quetiapine 500 mg daily were continued.

Given that Charlie presented with 4 episodes of severe manic symptoms with psychotic features after administration of intrathecal MTX, a causal association was assumed between the intrathecal MTX and development of these symptoms. After significant discussions between psychiatry and hem/onc, the decision was made to switch ALL treatment from IT MTX to intrathecal cytarabine/hydrocortisone (IT ARAC/HCZ) with oral MTX.

As a result, Charlie continued to present psychiatrically stable with no acute affective or 

. Psychotropic medications were gradually tapered off until they were discontinued 3 months after discharge. As per chart review, he remained psychiatrically stable over the next 2 years.

It is worth noting that Charlie received steroids in addition to IT MTX before the onset of first manic episode. No steroids, however, were given in combination with IT MTX prior to subsequent episodes. When treatment was switched to intrathecal steroid (IT ARAC/HCZ) with oral methotrexate, he remained psychiatrically stable with no further manic episodes reported.

In children with acute lymphoblastic leukemia, the addition of methotrexate to treatment protocols has been found to be beneficial in preventing central nervous system relapse.

 Methotrexate is a folate antagonist that is used for treating a variety of medical conditions including psoriasis, rheumatoid arthritis, and other 

Methotrexate inhibits dihydrofolate reductase (DHFR), the enzyme that reduces folic acid to tetrahydrofolic acid.

 The inhibition of DHFR by folate antagonists (methotrexate) results in a deficiency in the cellular pools of thymidylate and purines, and thus a decrease in nucleic acid synthesis. Therefore, methotrexate interferes with DNA synthesis, repair, and cellular replication. It also markedly interferes with transmethylation reactions, which are crucial for the formation of proteins, lipids, and also myelin, presumably leading to demyelination of nervous tissues.

Few mechanisms of precipitation of manic symptoms by methotrexate have been hypothesized. One possible cause is the interference of folate metabolism, as folic acid is used in the body to manufacture serotonin and dopamine neurotransmitters. Other postulations include interference in glutaminergic neurotransmission (increased release in glutamate and aspartate) by high levels of homocysteine and sulfur-containing amino acids, which is caused by the interference in folate metabolism.

 Glutaminergic neurotransmission is implicated in the pathophysiology of bipolar affective disorder and some studies report patients with manic episodes show elevated glutamate and glutamine.

Cytotoxic agents including methotrexate are potent neurotoxins. Although neurotoxicity has been observed with high dose oral or intrathecal methotrexate, to date there have been no published reports in the literature in which methotrexate precipitated a 

 in a patient with no prior history of bipolar disorder.

There are multiple drugs that are implicated in the development of manic symptoms, including antidepressants, steroids, levodopa, amphetamine, and phencyclidine, but methotrexate is not commonly implicated.

 In Charlie’s case, the contingency of the symptoms on methotrexate use and improvement on withdrawal of the drug and treatment of the manic episode suggest a causal relationship. 

ADHD has been genetically linked to bipolar disorder,

 and that may offer an explanation, at least in theory, about why this particular patient was more vulnerable to developing manic episodes.

In cases where mania is thought to be precipitated by IT MTX, we would recommend using an alternative medication or route of administration in addition to the use of psychotropic medications to manage the acute manic symptoms as appropriate.

To our knowledge, this is the first case report of acute onset mania in a patient with no prior personal or family history of bipolar disorder during IT MTX. It adds to the limited literature of methotrexate-induced mania in patients with previously stable bipolar disorder. Collectively, these reports contribute to the poorly understood relationship between bipolar disorder and treatment with cytotoxic agents, such as methotrexate.

is a child and adolescent psychiatrist, as well as an adjunct clinical assistant professor of psychiatry at Indiana University School of Medicine.

is an assistant professor at Emory University School of Medicine and is the Program Director for Emory’s Child and Adolescent Psychiatry Fellowship Program.

is the medical director for the psychiatry consultation-liaison service for Children’s Healthcare of Atlanta and adjunct assistant professor at Emory University School of Medicine.

is an assistant professor at Emory University School of Medicine.

1. Bedford Laboratories. Methotrexate for injection prescribing information. 2012. 

https://docs.boehringer-ingelheim.com/Prescribing%20Information/PIs/Ben%20Venue_Bedford%20Labs/55390-031-10%20MTX%2050MG/5539003110

2. Hariram J, Jegan Y. Contribution of methotrexate in precipitation of manic episode in bipolar affective disorder explored: a case report. 

3. Bührer C, Henze G, Hofmann J, et al. Central nervous system relapse prevention in 1165 standard-risk children with acute lymphoblastic leukemia in five BFM trials. 

4. Raimondi MV, Randazzo O, La Franca M, et al. DHFR inhibitors: reading the past for discovering novel anticancer agents. 

5. Vezmar S, Becker A, Bode U, Jaehde U. Biochemical and clinical aspects of methotrexate neurotoxicity. 

6. Sanacora G, Rothman DL, Mason G, Krystal JH. Clinical studies implementing glutamate neurotransmission in mood disorders. 

7. Michael N, Erfurth A, Ohrmann P, et al. Acute mania is accompanied by elevated glutamate/glutamine levels within the left dorsolateral prefrontal cortex. 

8. Ongür D, Jensen JE, Prescot AP, et al. Abnormal glutamatergic neurotransmission and neuronal-glial interactions in acute mania. 

9. Gigante AD, Bond DJ, Lafer B, et al. Brain glutamate levels measured by magnetic resonance spectroscopy in patients with bipolar disorder: a meta-analysis. 

10. Preda A, Shapiro B, Bienenfeld D. Substance-induced mood disorder. 

https://emedicine.medscape.com/article/286885-overview

11. Osser DN. ADHD in patients with bipolar disorder: genetics, diagnosis, and treatment. 

https://www.psychiatrictimes.com/view/adhd-bipolar-genetics-diagnosis-treatment

A case report and literature review of intrathecal methotrexate-induced mania.

 Can This Cancer Treatment Cause Manic Episodes?

A randomised controlled trial of dietary improvement for adults with major depression (the 'SMILES' trial).

2. Faraone SV, Biederman J, Spencer TJ, et al. 

Comparing the efficacy of medications for ADHD using meta-analysis.

4. Opie RS, O’Neil A, Jacka FN, et al. 

A modified Mediterranean dietary intervention for adults with major depression: dietary protocol and feasibility data from the SMILES trial.

5. Chang SC, Cassidy A, Willett WC, et al. 

Dietary flavonoid intake and risk of incident depression in midlife and older women.

Tea consumption and the risk of depression: a meta-analysis of observational studies.

7. Grassi D, Socci V, Tempesta D, et al. 

Flavanol-rich chocolate acutely improves arterial function and working memory performance counteracting the effects of sleep deprivation in healthy individuals.

8. Bowtell JL, Aboo-Bakkar Z, Conway ME, et al. 

Enhanced task-related brain activation and resting perfusion in healthy older adults after chronic blueberry supplementation.

9. Conner TS, Brookie KL, Carr AC, et al. 

Let them eat fruit! The effect of fruit and vegetable consumption on psychological well-being in young adults: a randomized controlled trial.

10. Morris MC, Tangney CC, Wang Y, et al. 

MIND diet associated with reduced incidence of Alzheimer's disease.

The effects of probiotics on depressive symptoms in humans: a systematic review.

12. Morris MC, Tangney CC, Wang Y, et al. 

MIND diet slows cognitive decline with aging

13. Topiwala A, Allan CL, Valkanova V, et al. 

Moderate alcohol consumption as risk factor for adverse brain outcomes and cognitive decline: longitudinal cohort study.

This article was originally posted on September 15, 2017, and has since been updated. -Ed.

Although supported by basic science, it’s still a sea change to think that diet can treat depression. Some research puts that idea to the test.

Can Food Treat Depression?

Intra-Cellular Therapies announced that it has recently submitted supplemental New Drug Applications (sNDAs) to the US Food and Drug Administration (FDA) for 2 indications for CAPLYTA (lumateperone), the first as monotherapy, the second as adjunctive therapy with lithium or valproate for the treatment of depressive episodes associated with bipolar I or II disorder in adults. If approved, CAPLYTA would be the first therapy indicated for the treatment of depressive episodes associated with bipolar I or II disorder both as monotherapy and as adjunctive therapy in adults.

“Bipolar I and II disorders are severe mental health conditions that affect approximately 11 million adults in the US and there remains a significant need for more treatment options,” Sharon Mates, PhD, Chairman and CEO of Intra-Cellular Therapies, said to the press. “We believe CAPLYTA has the potential to be an important option for patients in the treatment of bipolar depression. We look forward to bringing CAPLYTA to market, if approved, for the treatment of bipolar depression.”

Intra-Cellular Therapies conducted 2 positive phase 3 studies, Study 402 and Study 404, which form the basis of the sNDAs. In these studies, lumateperone 42 mg demonstrated a favorable safety and tolerability profile, with the most common adverse events being somnolence, dizziness, and nausea. The findings were consistent with previous studies in schizophrenia. Rates of akathisia, restlessness, and extrapyramidal symptoms were similar to placebo.

Results from Study 404 have been presented at scientific conferences already, and results from Study 402 will be presented at the American Psychiatric Association 2021 annual meeting in May.

The company anticipates an FDA target action date for the sNDAs in the second half of 2021.

1. BioSpace. Intra-Cellular Therapies applies for FDA approval of CAPLYTA® (lumateperone) for the treatment of bipolar depression. News release. February 22, 2021. 

https://www.biospace.com/article/releases/intra-cellular-therapies-applies-for-fda-approval-of-caplyta-lumateperone-for-the-treatment-of-bipolar-depression/

If approved by the FDA, this treatment would be the first therapy for treating depressive episodes in both bipolar I and II disorder in 2 different forms. 

The First of Its Kind: A New Bipolar Depression Treatment 

Susan J. Noonan, MD, MPH, talks about how finding a community and sharing experiences can help people going through an episode. 

is a physician consultant and Certified Peer Specialist in the Department of Psychiatry at McLean Hospital and the Massachusetts General Hospital. She is the author of four books and a blog on managing depression, most recently 

Helping Others With Depression: Words to Say, Things to Do (December 2020)

. Dr Noonan offers peer counseling to fellow patients, including physicians and other professionals, and can be confidentially reached through her website at 

When dealing with a serious mental illness, speaking out and sharing common experiences can help healing. 

Living Through an Episode

Literature is emerging on the effects of the coronavirus disease 2019 (COVID-19) pandemic on patients with bipolar disorder. This is part of the much larger literature on assessment and management of mental disorders during the 

Our group of 11 clinicians at the US Department of Veterans Affairs Bipolar Disorders Telehealth Program recently 

 of lessons learned from using telehealth modalities (videoconferencing and telephone contact) with more than 3000 veterans whose caregivers submitted consultation requests.

 is the way many, if not most, patients currently are being seen by clinicians. Many patients will continue to use this method even after the pandemic has waned. Telehealth has some specific effects on patients with bipolar disorder.

Video sessions and calls generally are very much welcomed by patients who are isolated to various degrees because of COVID-19. Their usual social outlets are diminished, and their access to in-person visits with clinicians is much reduced or eliminated. Hence, contact with an upbeat, thorough, authoritative, and supportive consulting clinician can have a tremendous effect in reassuring patients that help is available. In fact, 

 may diminish immediately during the call.

Effort must be made, however, to deal effectively with wireless connectivity issues that may render speech garbled with dropped words or pronunciations that are difficult to understand.

 It is important to slow down the conversation, adjust volume or microphone or video placement, be mindful of the time lag that can occur between speech and the transmission of the speech, and avoid interrupting the patient by responding too quickly. Video and phone transmission might make it difficult to determine if the patient is becoming tearful or 

, and it is important to ask if this is occurring.

Another issue associated with the pandemic is the loss of usual routines of behavior associated with previous mood states before isolation can result in new outlets (eg, buying online instead of in stores during manias). The clinician should be prepared to ask questions to uncover new syndromic behaviors.

 issues that are relatively unique to the COVID-19 era were summarized in a recent review by experts from Spain.

 Medication adherence is often reduced during isolation, so it is important (after establishing a therapeutic alliance using some of the previously noted suggestions) to inquire about adherence. Similarly, after examining the possible causes of nonadherence (eg, real or feared adverse effects, the feeling of being controlled by the medication, missing periods of euphoria), clinicians should educate their patients about the importance of adherence. Help may be needed from significant others in the household to monitor adherence, with the patient’s permission.

Substance use disorders may increase in severity in the isolation setting, and these should be ruled out or managed, if necessary. Patients may be fearful of initiating new medications without an in-person encounter, especially if bloodwork is required or patients have concerns about entering a medical facility for

 The importance of lithium levels and kidney function tests will need to be reiterated and the benefits weighed against the risks associated with going to get the tests, which can be minimized with appropriate social distancing and masks.

 with medications used in the treatment of patients who have COVID-19, if the patient requires hospital treatment.

 Dexamethasone can induce mood switches to mania or depression. Dexamethasone’s metabolism is induced by carbamazepine and, to a lesser extent, by oxcarbazepine. Initiation of these anticonvulsant mood stabilizers should therefore be avoided if possible. They also induce the metabolism of remdesivir, and carbamazepine may add to the risk of liver dysfunction caused by this antiviral agent. If the patient is already on one of these mood stabilizers, appropriate dosage adjustments of the COVID-19 drugs and lab monitoring will be needed. Chloroquine and hydroxychloroquine should be avoided in patients with COVID-19 and bipolar disorder because they increase risk of mania, psychosis, and 

is associate professor of psychiatry, Harvard Medical School, and co-lead psychiatrist at the US Department of Veterans Affairs, National Telemental Health Center, Bipolar Disorders Telehealth Program, Brockton, Massachusetts.

1. Bojdani E, Rajagopalan A, Chen A, et al. 

COVID-19 pandemic: impact on psychiatric care in the United States

2. Burgess C, Miller CJ, Franz A, Abel EA, et al. 

Practical lessons learned for assessing and treating bipolar disorder via telehealth modalities during the COVID-19 pandemic

4. Hernández-Gómez A, Andrade-González N, Lahera G, Vieta E. 

Recommendations for the care of patients with bipolar disorder during the COVID-19 pandemic

As we learn about the effect of COVID-19 on patients with bipolar and other psychiatric disorders, clinicians should be prepared to ask questions to uncover new syndromic behaviors.

COVID-19 Pandemic’s  Effects on Assessment & Psychopharmacological Management

A new test screens for bipolar disorder with respectable accuracy

How to Screen for Bipolar Disorder in 2 Minutes

There is evidence for an increased prevalence of comorbid substance use disorders (SUDs) in patients with bipolar disorder (BD), even when 

 found that the lifetime prevalence of alcohol abuse or dependence in bipolar I and II disorder was 46% and 39%, respectively. A more 

 of 43,000 respondents found a 24% 12-month and 56% lifetime prevalence of any alcohol use disorders (AUD) in patients with bipolar I disorder.

 that comorbid AUD is associated with a more complicated illness course and poorer outcomes in patients with BD.

Most studies of comorbid BD and AUD have been retrospective, and few prospective studies have differentiated between bipolar I and II disorders. Using the COGA sample (Collaborative Study on Genetics in Alcoholism), 

 directly compared patients who had bipolar I and II disorders with and without comorbid alcohol dependence. These patients were assessed at baseline and then prospectively reinterviewed after 5 years.

COGA enrolls treatment-seeking probands with 

 (and their relatives) at 6 centers in the United States. Exclusion criteria are life-threatening medical disorders, repeated intravenous drug use, and an inability to speak English. Patients were interviewed at baseline, as well as after approximately 5 years using the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA). The SSAGA contains an assessment of 17 DSM-IV diagnoses, including BD, as well as the timing of symptom onset and remission.

Altogether, 228 participants with bipolar I disorder or bipolar II disorder were identified. One-hundred seventy-two patients had a comorbid diagnosis of alcohol dependence (N = 56 with bipolar II [Group 2] and 116 with bipolar I [Group 4]). Fifty-six individuals did not have 

 (N = 20 with bipolar II [Group 1] and N = 36 with bipolar I [Group 3]). One-hundred twenty-one (53%) of patients were reassessed at a mean of 5.7 years after the initial interview, including 13, 30, 17, and 61 patients in Groups 1, 2, 3, and 4, respectively. All participants were in a euthymic mood state at the time of the SSAGA interview. Between-group differences were evaluated using chi-square tests for categorical data and 1-way analysis of variance (ANOVA). Repeated-measures ANOVA was used to compare continuous variables over time.

At baseline, the mean age was 36 years; 52% were female, and 74% were Caucasian. Regarding patients with alcohol dependence, those with bipolar II disorder had a higher rate of alcohol-related liver disease than those with bipolar I disorder (10.7% versus 1.7%). Individuals with bipolar I disorder were significantly more likely to have had outpatient treatment than those with bipolar II disorder (48% versus 29%). Otherwise, there were no differences in age of onset of alcohol dependence, treatment, alcohol-related violence and physical problems, and other psychiatric comorbidity.

There were no significant differences in age of onset of mania/hypomania and depression between all groups. There were also no significant difference in the proportion of patients with lifetime suicidal ideation and suicide attempt between patient groups. However, 

 and comorbid alcohol dependence had a greater number of lifetime suicide attempts than patients without alcohol comorbidity (5 versus 1.5), although this finding was not statistically significant. Patients with bipolar I disorder and alcohol dependence had a significantly lower global assessment of functioning score (58) than the other groups (range 67-75).

During the 5-year follow-up, regarding patients with alcohol dependence, subjects with bipolar I disorder had a significantly higher prevalence of 

 than those with bipolar II disorder (31.1% versus 13.3%). Individuals with comorbid bipolar I disorder and AUD had a significantly higher prevalence of suicidal ideation (46% versus 10% to 29%) and suicide attempt (18% versus 0%) than the other groups. Patients with bipolar I disorder and alcohol dependence also had more affective symptoms and significantly lower global assessment of functioning score (59) than the other groups (range 62-77).

The authors concluded that individuals with bipolar I disorder and comorbid alcohol dependence had a worse course of mood illness. One limitation of the 

 include that the target of the COGA study was patients with alcohol dependence, and therefore only about one-quarter of the patients with BD did not have comorbid alcohol dependence. Another limitation is that almost half of the participants could not be re-interviewed after 5 years, and there is the potential for selective recall bias in those who were interviewed. A primary strength of the study is consideration of patients with bipolar I and bipolar II disorders, separately.

There is evidence from this prospective study that there is a more severe course of bipolar illness in patients with bipolar I disorder and comorbid alcohol dependence. These patients may require comprehensive treatment for psychiatric and SUDs in order to improve symptomatic and functional outcomes.

is professor in the Department of Psychiatry and Health Behavior, Augusta University, 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, the Brain and Behavior Research Foundation, and the Stanley Medical Research Institute.

Comorbidity of mental disorders with alcohol and other drug abuse: results from the epidemiologic catchment area (ECA) study

2. Grant BF, Stinson FS, Hasin DS, et al. 

Prevalence, correlates, and comorbidity of bipolar I disorder and axis I and II disorders: results from the National epidemiologic survey on alcohol and related conditions

Impact of substance abuse on the course and treatment of bipolar disorder

4. Preuss UW, Hesselbrock MN, Hesselbrock VM. 

A prospective comparison of bipolar I and iI subjects with and without comorbid alcohol dependence from the COGA dataset

Are there differences in the clinical course of bipolar I and bipolar II disorder with and without comorbid alcohol use disorder?

Don't Raise a Glass: Alcohol Dependence Complicates Bipolar Disorder

Crisis Assistance Helping Out On The Streets

) is a mobile crisis-intervention program that was created in 1989 as a collaboration between White Bird Clinic and the City of Eugene, Oregon. Its mission is to improve the city’s response to mental illness, substance abuse, and homelessness.

, which was formed in 1969 by members of the 1960s countercultural movement. They were interested in alternative and experimental approaches to addressing societal problems. Today, White Bird Clinic operates more than a dozen programs, primarily serving low-income and indigent clientele.

The CAHOOTS model was developed through discussions with the city government, police department, fire department, 

 (EMS), mental health department, and others. The name CAHOOTS is based on the irony of White Bird Clinic’s alternative, countercultural staff collaborating with law enforcement and mainstream agencies for the common good.

When it began, CAHOOTS had very limited availability in 

e. It has grown into a 24-hour service in 2 cities, Eugene and Springfield, with multiple vans running during peak hours in Eugene. The program—which now responds to more than 65 calls per day—has more than quadrupled in size during the past decade due to societal needs and the increasing popularity of the program.

Programs based on the CAHOOTS model are being launched in numerous cities, including Denver, Oakland, Olympia, Portland, Maine, and others. 

 (Senators Ron Wyden of Oregon and Catherine Cortez Masto of Nevada have proposed a bill that would give states $25 million to establish or build up existing programs.)

When CAHOOTS was formed, the Eugene police and fire departments were a single entity called the Department of Public Safety. CAHOOTS was designed to be a hybrid service capable of handling noncriminal, nonemergency police and medical calls, as well as other requests for service that are not clearly criminal or medical.

Eugene’s police and fire departments eventually split. CAHOOTS was absorbed into the police department’s budget and dispatch system. It continues to respond to requests typically handled by police and EMS with its integrated health care model.

 worker who is skilled in counseling and de-escalation techniques, and a medic who is either an EMT or a nurse. This pairing allows CAHOOTS teams to respond to a broad range of situations.

For example, if an individual is feeling suicidal and they cut themselves, is the situation medical or psychiatric? Obviously, it is both, and CAHOOTS teams are equipped to address both issues. Typically, such a call involving an individual who engaged in self-harm would result in a response from police and EMS. This over-response is rarely necessary. It can also be costly and intimidating for the patient. They are not criminals, and their wounds are often not serious enough to require more than basic first aid in the field. These patients are usually seeking help, and a CAHOOTS team is trained to address both the 

 of the patient while alleviating the need for police and EMS involvement. If necessary, CAHOOTS can transport patients to facilities such as the emergency department, crisis center, detox center, or shelter free of charge.

When concern for a patient is not so severe that a clinician feels compelled to call the police, there are options.

Bipolar Disorder