David N. Osser, MD

There appears to be some confusion regarding the efficacy of topiramate in bipolar disorder. Some prescribers think it is effective for mania, depression, or simply for “mood.” The 

does not support this: all studies found no efficacy.

 Also, topiramate has a significant adverse effect burden, including the infrequent but serious problems of kidney stones (in more than 2% of patients),

 glaucoma, and suicidal ideation, and the more common problems (disliked by patients) of cognitive and memory impairment, numbness and tingling in the extremities, and hyperchloremic acidosis (present in up to 40% of patients

—check electrolytes and you will see) which can give a variety of non-specific symptoms that include dizziness, nausea, and fatigue. Topiramate is FDA approved for seizures and for migraine prophylaxis.

There are some off-label proposed uses for topiramate in comorbidities that are common in patients with 

. It has been used as an adjunct to olanzapine to mitigate or even prevent weight gain.

 This is not recommended as something to do routinely (because of all those adverse effects), but at times this can be helpful and worth the risks. Topiramate in low doses (up to 92 mg) is a component of a weight loss combination product (with phentermine) that is on the market.

Some patients with bipolar disorder who experience weight gain also have binge eating disorder (BED). There is only one FDA-approved medication for this: lisdexamfetamine. However, patients with bipolar disorder not currently on a good dose of a mood stabilizer and who have comorbid BED would likely not benefit from lisdexamfetamine or any other stimulant (nor with any antidepressant, some of which also have 

 Topiramate has 2 positive studies in BED with good results so you might think of it for them.

Some substance abuse disorders (SUDs) may benefit from topiramate for prevention of relapse. There may be mild benefit in alcohol use disorder,

 and there are 2 positive studies of patients with 

use disorder, only 1 of which showed benefit at end point—at doses up to 300 mg daily.

 Note that all of these studies used substantial doses of topiramate. One encounters patients on low doses like 25 mg twice a day. These may be placebo-level doses for any of the possible SUD indications.

Several trials have examined the effect of topiramate on posttraumatic stress disorder (PTSD). In 2 studies, there was no difference from placebo, but 1 study conducted in Brazil on 70 civilian patients found a good effect size. The reduction in the Clinician-Administered PTSD scale was 58 on topiramate and 32 on placebo, p = 0.008.

Three small placebo-controlled trials of topiramate at up to 200 mg daily in patients with borderline personality disorder (BPD) are all from the same research group in Germany/Austria. 

 in hostility, interpersonal sensitivity, and anxiety symptoms were reported, larger than have been seen in other psychopharmacology studies of BPD.

 Although the papers identify no funding source, the UK NICE Guideline Development Group (GDG), suspicious about the large effect sizes, attempted without success to get more information about the funding from the authors and the publishing journals. Their interesting 

was “. . . as the GDG were unable to gain clarity in this regard, they took the decision not to consider their trials when drawing up their conclusions.”

 Clearly, these studies need replication.

is Associate Professor of Psychiatry, Harvard Medical School, and Consulting Psychiatrist, US Department of Veterans Affairs, National Telemental Health Center, Bipolar Disorders Telehealth Program, Brockton, MA. The author reports no conflicts of interest concerning the subject matter of this article.

1. Pigott K, Galizia I, Vasudev K, et al. 

Topiramate for acute affective episodes in bipolar disorder in adults

2. Dell’Oro VG, Belotti EA, Simonetti BG, et al. Metabolic disturbances and renal stone promotion on topiramate: a systematic review.

3. Narula PK, Rehan HS, Unni KES, Gupta N. Topiramate for the prevention of olanzapine associated weight gain and metabolic dysfunction in schizophrenia: a double-blind, placebo-controlled trial. 

4. McElroy S, Hudson JI, Capece JA, et al. 

Topiramate for the Treatment of Binge Eating Disorder Associated With Obesity: A Placebo-Controlled Study

5. Palpacuer C, Duprez R, Huneau A, et al. Pharmacologically Controlled Drinking in the Treatment of Alcohol Dependence or Alcohol Use Disorders: A Systematic Review with Direct and Network Meta-Analyses on Nalmefene, Naltrexone, Acamprosate, Baclofen and Topiramate. 

Topiramate for Cocaine Dependence: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

7. Yeh MSL, Mari JJ, Costa MCP, et al. A double-blind, randomized controlled trial to study the efficacy of topiramate in a civilian sample of PTSD. 

8. Loew TH, Nickel MK, Muehlbacher M, et al. 

Topiramate treatment for women with borderline personality disorder: a double-blind, placebo-controlled study

9. National Institute for Clinical Excellence (NICE). Borderline Personality Disorder: Treatment and Management. January 28, 2009. Accessed July 13, 2020. www.

Articles

There are some off-label proposed uses for topiramate in comorbidities that are common in patients with bipolar disorder. What does the evidence say?

Topiramate in Bipolar Disorder and Comorbidities: The Myths and the Evidence

Valproate/divalproex appears to be considerably overused in the US; the use of lithium, second-generation antipsychotics, and carbamazepine should be more prominent in treatment decisions for patients with bipolar mania.

Valproate/divalproex was approved by the FDA for use in bipolar mania with the publication of a major study in 1994 that showed efficacy. It was heavily marketed and entered the mainstream practice in the US. It has been used less in Europe and even less in Japan where carbamazepine is more popular as an alternative to lithium. In the 1970s, Japanese researcher Teruo Okuma, MD, PhD, was the first to demonstrate the effect of carbamazepine in mania.

As there have been more studies, the evidence base for the efficacy of this product has become less and less impressive. In the last 2 published placebo-controlled trials of divalproex in acute mania (1 in adults, 1 in adolescents and young adults), there were no differences from placebo; and, in the 

published just before those, the effects were statistically significant but quite small.

 Meta-analyses of controlled studies of medications for acute mania find it to have a 

 size than lithium, carbamazepine, and antipsychotics.

Maintenance trials have not shown efficacy, and the medication does not have FDA approval as a maintenance treatment for bipolar disorder. Its use for that purpose, although common, is off-label. Valproate/divalproex is also not approved for treatment of acute bipolar depression nor for prevention of depressive episodes. However, there are a few small studies that 

that it could work for bipolar depression; larger studies are needed.

One group of patients with bipolar disorder that seem to fare better on valproate includes those with acute mixed mania (ie, meeting full criteria for mania but having 3 or more symptoms of depression concomitantly). Valproate may be preferred over lithium for such patients.

Clinicians often choose valproate because of a perception that it has a milder adverse effect profile than other bipolar medications. However, head-to-head studies indicate that 1 very important adverse effect—weight gain—is greater with valproate than with lithium, olanzapine, and quetiapine.

 The risk of suicidal behaviors is twice as high on anticonvulsants such as valproate compared with controls, whereas substantial evidence finds reduced risk of suicidality on lithium. Liver dysfunction and, less commonly, pancreatitis, thrombocytopenia, and polycystic ovaries are other significant adverse effect issues with valproate. It has the most teratogenicity of any medication used in bipolar disorder and has been 

by experts to be a last resort medication for any woman of child-bearing potential.

In conclusion, valproate/divalproex appears to be considerably overused in the US. Clinicians should think of lithium, second-generation antipsychotics, and carbamazepine more prominently in selecting medication for patients with bipolar mania. Patients should be informed of the evidence-base for efficacy and FDA approval status before being prescribed valproate for acute illness and especially for maintenance usage.

 is Associate Professor of Psychiatry, Harvard Medical School, and Consulting Psychiatrist, US Department of Veterans Affairs, National Telemental Health Center, Bipolar Disorders Telehealth Program, Brockton, MA.

This article was posted ahead of print on June 16, 2020, under the title "Valproic Acid: Its Role in Bipolar Disorder," and has since been updated. -Ed

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

. 2014;22:274-294.
2. Cipriani A, Barbui C Salanti G, et al. 

Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis

. 2011;378:1306-1315.
3. Osser DN, Wang D. 

The psychopharmacology algorithm project at the Harvard South Shore Program: an update on bipolar depression

. 2019; DOI: 10.1111/bdi.12860.
4. Balon R, Riba M. Should women of childbearing potential be prescribed valproate? A call to action. 

. 2016:77:525-526.
5. Sher J, Frank JW, Doi L, de Caestecker L. Failures in reproductive health policy: overcoming the consequences and causes of inaction. 

Valproic Acid: Overused in Bipolar Disorder?

Do you prescribe antidepressants for your patients with bipolar depression? If so, think again, and consider results from the Systematic Treatment Enhancement Program–Bipolar Disorder (

) studies. This was the largest federally funded group of studies of bipolar disorder treatment, and they included important randomized clinical trials involving subsamples of the 4360 patients enrolled.

Among the significant findings were the following:

1. Antidepressants (bupropion, paroxetine) are not more effective than placebo for bipolar depression (24% for the antidepressants versus 27% for the placebo in a 6-month trial).1 The antidepressants, when added to a mood stabilizer, did not induce more switches into mania (10% versus 11%), but the patients who participated in the study were probably at very low risk for switching. However, patients with bipolar depression with mixed features (defined as having 2 or more manic symptoms [eg, agitation and racing thoughts] with their depression) developed manias over the next several months that were more severe as compared with placebo-treated patients.

2. A group of 86 patients with bipolar disorder who responded to an antidepressant when depressed were identified. Some were rapid cyclers (4 or more episodes per year). All of the patients were also prescribed mood stabilizers such as lithium, valproate, or a second-generation antipsychotic. These patients were randomized to stay on the antidepressants or discontinue them. The patients with rapid cycling who were continued on their antidepressant had triple the number of depressions per year compared with those without rapid cycling. Yet, there was no difference in the rate of depressions between rapid and non-rapid cycling in the antidepressant discontinuation group. Thus, depressive morbidity and cycling were worsened by continuation of an antidepressant in patients with rapid cycling.

 were collected on the first 1500 patients looking for evidence of the antidepressant-associated chronic irritable dysphoria (ACID) syndrome described in previous case reports.

 It had been proposed that ACID was caused by treating patients who had bipolar depression with an antidepressant. The patient sample included 63% bipolar I patients with depression; most of the remaining patients had bipolar II. The researchers identified 83 patients in whom a depressive episode developed during the study period and for whom there was at least 1 year of follow-up information. Those who received an antidepressant for their depression had a 10-fold higher risk for ACID than the patients who were antidepressant free. ACID did not seem to occur in the natural course of bipolar disorder; it only occurred in those who received antidepressants.


Findings from STEP-BD studies indicate that antidepressants should be avoided in most cases when treating acute depression in patients with bipolar disorder. Rather, one should choose from among 5 medications with a reasonable evidence-base for effectiveness and safety in treating or at least preventing bipolar depressions, namely: lithium, quetiapine, lamotrigine, lurasidone, and cariprazine—or combinations of these.

1. Sachs GS, Neirenberg AA, Calabrese JR, et al. 

Effectiveness of adjunctive antidepressant treatment for bipolar depression

2007;356:1711-1722.
2. El-Mallakh RH, VÃ¶hringer PA, Ostacher MM, et al. 

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

2015;184:318-321.
3 El-Mallakh RH, Ghaemi SN, Sagduyu K, et al.

 Antidepressant-associated chronic irritable dysphoria (ACID) in STEP-BD patients

This article was originally posted on April 24, 2020, and has since been updated. -Ed

Do you prescribe antidepressants for your patients with bipolar depression? If so, think again, and consider results from these studies.

The Case Against Antidepressants for Bipolar Depression: Findings from STEP-BD

We frequently encounter patients who use cannabis. More than 50 indications for medical marijuana are approved by various state governments, although no indications are FDA-approved. Marijuana is legal in 36 states-and 10 states allow recreational use-but regulation of the quality or purity of these products is minimal. Some patients are convinced that marijuana calms them, uplifts them, blunts their anxiety, enables them to sleep, and has other benefits like helping with pain. Many report that it is the only thing that is reliably helpful for neuropsychiatric symptoms, compared with prescribed medications. Notably, scores of nicotine users say the same thing: it is their coping strategy of choice for just about every stress or even their “only pleasure in life.” Others say the same things about benzodiazepines. Rhetorical question: What do these substances have in common?

Regardless of whatever short-term benefit patients perceive from cannabis, the evidence points clearly to an association between usage and worsening course of bipolar disorder over time. In a study of 4915 participants, Henquet et al.

 found a strong increased risk of manic symptoms associated with cannabis over a three year follow-up (after controlling for possible covariates). They also saw an earlier age of onset of bipolar disorder, greater overall illness severity, more rapid cycling, poorer life functioning, and poorer adherence with prescribed treatments.

 evaluated the subsequent course of patients with bipolar disorder who stopped cannabis use after an illness episode and compared their outcome with patients with bipolar disorder who had never used cannabis and a group that continued to use. The total sample included 1922 patients. In a two year period, the continued users had significantly lower rates of recovery, greater work impairment, and fewer were living with a partner. The data were based on patient reports; given that fact, there was likely under-reporting and probably an underestimate of the association between cannabis use and lives worsened. A systematic review of the effects of cannabis on mood and anxiety disorders confirmed a negative association between cannabis use and long-term outcomes.

Some patients exhibit psychotic symptoms after cannabis use. A recent study found that schizophrenia or bipolar disorder developed in many of these patients.

 This happened in 47% of patients who became psychotic on cannabis over the next four years. This was the highest incidence of conversion after initial psychosis following use of various substances: the second highest was with amphetamine, at 32%. More patients converted to schizophrenia than to bipolar. As for any possible benefits, a recent review concluded that the evidence supporting use of cannabis for psychotic (or other psychiatric) disorders is “very low” and “inadequate.”

The non-psychiatric medical benefits of cannabis are also very thinly evidenced despite outsized claims to the contrary.

 It is said to be “irresponsible” to encourage patients addicted to opiates to switch to cannabis for their problems with pain.

Thus, it seems that patients with bipolar disorder should stay away from cannabis in all its forms. Quitting cannabis should be on the short list of interventions if patients are not doing well. This is a tough sell in today’s political environment regarding cannabis legalization. Many newspaper editorials and politicians support its beneficial effects and use. Clinicians should not back down and accept patients’ insistence on using this product; rather, they should continue efforts to educate and to consider the problem to be a serious one that potentially interferes with otherwise appropriate and effective bipolar treatments that may be offered.

1. Henquet C, Krabbendam L, de Graaf R, et al. Cannabis use and expression of mania in the general population. J Affect Disord. 2006;95:103-110.

2. Zorrilla I, Aguado J, Jaro JM, et al. Cannabis and bipolar disorder: does quitting cannabis use during manic/mixed episodes improve clinical/functional outcomes? Acta Psychiatrica Scand. 2015;131:100-110.
	3. Mammen G, Rueda S, Roerecke M, et al. Association of cannabis with long-term clinical symptoms in anxiety and mood disorders: a systematic review of prospective studies. J Clin Psychiatry. 2018;79:17r11839.

4. Starzer MSK, Nordentoft M, Hjorthoj C. Rates and predictors of conversion to schizophrenia or bipolar disorder following substance-induced psychosis. Am J Psychiatry. 2018;175:343-350.
	5. Radhakrishnan R, Ranganathan M, D’Souza DC. Medical marijuana: what physicians need to know. J Clin Psychiatry. 2019;80:45-47.

6. Hill JH. Medical use of cannabis in 2019. JAMA. 2019;322:974-975.

7. Humphreys K, Saitz R. Should physicians recommend replacing opioids with cannabis? JAMA 2019; 321(7): 639-640.

Regardless of whatever short-term benefit patients perceive from cannabis, the evidence points clearly to an association between usage and worsening course of bipolar disorder over time.

Cannabis: Patients With Bipolar Should Avoid Use

Do you need help persuading patients to try lithium? A major but often underemphasized benefit of lithium is its unique neuroprotective effects. Bipolar disorder seems to be a condition characterized by gradual progressive shrinkage in some areas of cortical gray matter as well as some tracks of white matter. These losses are associated with increased neurocognitive impairment. However, in patients who have been treated with long-term lithium, there is better preservation of white matter structural integrity.

 Reduction of gray matter volume in bipolar patients has been shown to be arrested, or even reversed to some degree, by lithium. No other mood stabilizers have this effect. Some ambivalent patients have been persuaded to accept lithium after reading the article by Giakoumatos and colleagues.

At the microcellular level (in rats), lithium is protective against neuronal apoptosis (destruction) and glutamate-induced cytotoxicity, and it promotes dendritic length and number in the hippocampus.

 The preservation of cognitive function in humans with bipolar disorder seems to occur through the brain-derived neurotrophic factor (BDNF) system: lithium markedly increases secretion of BDNF from cortical and hippocampal neurons and upregulates intracellular production of relevant proteins.

The evidence for lithium’s neuroprotection even extends to the prevention, treatment, or slowing of mild cognitive impairment, Alzheimer disease, Parkinson disease, and amyotrophic lateral sclerosis in non-bipolar patients.

 Even low-dose lithium has been found in preliminary studies to slow the progression of Alzheimer disease.

Given this information, it should not be surprising that the benefits of lithium treatment seem to exist for patients across the life span.

 However, there is no reason to wait: the long-term benefits seem greatest when lithium is started early in the course of the illness,

 perhaps because some of the brain structural losses may be irreversible. These mechanisms of lithium action also help explain the evidence that of all medication regimens used for bipolar treatment, lithium is the medication most likely to be maintained as a monotherapy over time. This has been demonstrated in surveys of bipolar patients receiving maintenance treatment in the US and in two European studies.

Dr Osser is Associate Professor of Psychiatry, Harvard Medical School, and Consulting Psychiatrist, US Department of Veterans Affairs, National Telemental Health Center, Bipolar Disorders Telehealth Program, Brockton, MA.

 Giakoumatos CI, Nanda P, Mathew IT, et al. Effects of lithium on cortical thickness and hippocampal subfield volumes in psychotic bipolar disorder. 

Nunes MA, Schowe NM, Monteiro-Silva KC, et al. Chronic microdose lithium treatment prevented memory loss and neurohistopathological changes in a transgenic mouse model of Alzheimer disease. 

De-Paula VJ, Gattaz WF, Forlenza OV. Long-term lithium treatment increases intracellular and extracellular brain-derived neurotrophic factor in cortical and hippocampal neurons at subtherapeutic concentrations. 

Forlenza OV, De-Paula VJ, Diniz BS. Neuroprotective effects of lithium: implications for the treatment of Alzheimer disease and related neurodegenerative disorders. 

Young RC, Mulsant BH, Sajatovic M, et al. GERI-BD: A randomized double-blind controlled trial of lithium and divalproex in the treatment of mania in older patients with bipolar disorder. 

Kessing LF, Vradi E, Andersen PK. Starting lithium prophylaxis early v. late in bipolar disorder. 

Hayes JF, Marston L, Walters K, et al. Lithium vs. valproate vs. olanzapine vs. quetiapine as maintenance monotherapy for bipolar disorder: a population-based UK cohort study using electronic health records. 

Do you need help persuading patients to try lithium?

The Neuroprotective Effects of Lithium

There appears to be some confusion regarding the efficacy of aripiprazole in bipolar mania and depression and for preventing bipolar episodes. Aripiprazole is approved by the US Food and Drug Administration as a treatment for acute mania. It is not one of the more robustly efficacious agents for mania, however; haloperidol, risperidone, olanzapine, and quetiapine (in that order) top the list in a meta-analysis by Cipriani and collegues.

Haloperidol is not recommended as a first-line agent because of the risk of tardive dyskinesia (more common in mood disorder patients versus schizophrenia). Moreover, evidence indicates that it is the antimanic agent associated with the highest risk switching to a depressive episode after resolution of the mania.

 Aripiprazole had two early trials in which it did not differ from placebo in mania, which lowered its effect size compared with other options. Efficacy was found in studies using 15 to 30 mg doses.

In bipolar depression, the situation is a little more complicated, but in short, aripiprazole has not been found to be effective. Two large manufacturer-sponsored trials failed to show any difference from placebo after eight weeks of treatment.

 It is not FDA-approved for bipolar depression. What is confusing for clinicians is that aripiprazole is well-known for its antidepressant effect as an augmenter of selective serotonin reuptake inhibitors in unipolar depression. It was heavily advertised for that purpose (at least, until it recently became generic). It has never been studied as an augmentation for antidepressants in bipolar depression.

The use of antidepressants (with or without augmenters) in bipolar depression remains controversial at best. The exception is the combination of olanzapine and fluoxetine, which is effective and FDA-approved for bipolar depression, although one usually wants to avoid it because olanzapine has severe metabolic adverse effects and induces insulin-resistance.

In the 8-week aripiprazole studies, there was separation from placebo in some of the earlier weeks, but by week 8 there was no difference (number needed to treat = 44).

 Dosage at endpoint reached a mean of 16.5 mg daily. Some have speculated that if they had used lower doses (eg, starting at 2 to 5 mg and titrating to 5 to 10 mg), the researchers might have found a more sustained antidepressant effect. The proposed mechanism is that at lower doses there could be less akathisia and it might have kept working on the depression over the full eight weeks. This is possible and deserves study.

However, in the one maintenance study of aripiprazole in bipolar disorder (which resulted in FDA-approval as a maintenance agent in bipolar disorder), there was significant benefit for reducing manic episodes over six months compared with placebo, but no efficacy in preventing depressions or mixed states with depressive symptoms.

Other antipsychotics used as monotherapy have been found effective for bipolar depression. These include quetiapine, lurasidone, and cariprazine (all FDA-approved). Lamotrigine and lithium have efficacy and FDA-approval as maintenance treatments in bipolar depression. Thus, for many patients with bipolar depressions, these five medications would be preferred over aripiprazole.

Dr Osser is Associate Professor of Psychiatry, Harvard Medical School, and Consulting Psychiatrist, US Department of Veterans Affairs, National Telemental Health Center, Bipolar Disorders Telehealth Program, Brockton, Mass.

1. Cipriani A, Barbui C, Slanti G, et al. Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple treatments meta-analysis. Lancet. 2011; 378:1306-1315.

2. Goikolea JM, Colom F, Torres I, et al. Lower rate of depressive switch following antimanic treatment with second-generation antipsychotics versus haloperidol. J Affect Disord. 2013;144:191-198.

3. Thase ME, Jonas A, Khan A, et al. Aripiprazole monotherapy in nonpsychotic bipolar I depression: results of 2 randomized, placebo-controlled studies. J Clin Psychopharm. 2008;28:13-20.

4. Keck PE Jr, Calabrese JR, McQuade RD, et al. A randomized, placebo-controlled 26-week trial of aripiprazole in recently manic patients with bipolar I disorder. J Clin Psychiatry. 2006;67:626-637.â

There appears to be some confusion regarding the efficacy of aripiprazole in bipolar mania and depression and for preventing bipolar episodes.

Clinical Updates From Bipolar Telehealth

Lamotrigine monotherapy has emerged as a possible treatment for bipolar depression. It is not associated with weight gain and is less likely to cause neurocognitive adverse effects and sedation. Most patients tolerate it well. It does carry a risk of dangerous rashes, but the risk is minimized by slow dosage titration and alert monitoring. The incidence of serious rash may also be less than previously reported (in particular, when faster dosage titration was used). The rate now appears to be 0.1% or less.

The evidence supporting lamotrigine usage for acute bipolar depression, however, is mixed. On the positive side, one double-blind, placebo-controlled study of lamotrigine (50 mg/d, 200 mg/d, or placebo) in bipolar I depression (n = 195) showed favorable results.

 At 50 mg, 41% of patients improved;on 200 mg, 51% responded; and 26% improved on placebo.

These positive findings about lamotrigine had been countered, however, by four negative studies that are large, industry-supported, double-blind, placebo-controlled clinical trials studying lamotrigine treatment in acutely depressed bipolar I and II patients. None of the four studies found a statistical difference between lamotrigine and placebo. As a result, lamotrigine did not receive Food and Drug Administation approval for acute bipolar depression. A meta-analysis of these five studies, however found a small benefit with an overall effect size of 0.27.

 In more severely ill patients (Hamilton 24 or more), lamotrigine had a greater separation from placebo (0.47) mostly because placebo effect was lower in this group. Lamotrigine was not better than placebo if the baseline Hamilton was lower than 24 (0.07 effect size). In another approach to predicting response, a small observational study showed better results at lamotrigine blood levels around 4 ng/mL.

The efficacy of lamotrigine as maintenance therapy is fairly robust. Two large, 18-month studies showed efficacy, enabling lamotrigine to obtain FDA approval for maintenance use.

 It had no efficacy for preventing mania, but at least it did not increase the risk of mania compared with placebo.

Lamotrigine has shown no efficacy in treating acute mania, which makes it less desirable than lithium, quetiapine, or cariprazine in that there will be no coverage for the manic/hypomanic phases. It also has no apparent benefit for suicidal ideation or behaviors. In fact, like all anticonvulsants, it carries a warning about possible increased risk of suicidality. On the other hand, its relatively benign side effect profile might make it a first choice for some patients, especially if the past hypomanias have been mild.

Lamotrigine might also be worth considering in women of childbearing potential. The teratogenic risk of lamotrigine is approximately 1% to 4%, the lowest among the antiepileptic medications. A large observational study found an odds ratio compared with controls of 1.3 for orofacial cleft abnormalities.

 If, after carefully weighing the options, lamotrigine is selected for these women, close monitoring of serum level is prudent as dosing and serum concentration dramatically differ depending on the stage of pregnancy.

 Calabrese JR, Bowden CL, Sachs GS, et al, for the Lamictal 602 Study Group. Double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. 

 Geddes JR, Burgess S, Hawton K, et al. Long-term lithium therapy for bipolar disorder: systematic review and meta-analysis of randomized controlled trials. 

 Kesebir S, Akdeniz F, Demir A, Bilici M. A comparison before and after lamotrigine use in long-term continuation treatment: effect of blood level. 

 Bowden CL, Calabrese JR, Sachs G, et al. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. 

 Calabrese JR, Bowden CL, Sachs, G, et al. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar I disorder. 

 Dolk H, Wang H, Loane M, et al. Lamotrigine use in pregnancy and risk of orofacial cleft and other congenital anomalies. 

The good, the bad, and the efficacy of lamotrigine.

Lamotrigine: Its Role in Bipolar Disorder

An international task force of experts in the diagnosis and treatment of bipolar disorder was recently convened to address concerns about DSM-5 criteria, particularly the definitions of manic episodes. This initiative was funded by the National Health and Medical Research Council of Australia; 64 individuals from 14 countries spanning five continents responded to a questionnaire probing different aspects of the criteria.

 The findings are pertinent for clinicians struggling to make the bipolar I and II diagnoses, which have been found to be both underdiagnosed and overdiagnosed in different studies. The consequences for patient outcomes with these missed diagnoses can be severe.

The DSM’s duration criteria is an area of concern. Currently, it includes seven days for mania and four days for hypomania. Patients with only brief episodes who meet phenotypic criteria are excluded from the diagnosis, and a lot of time is spent with patients struggling to find if they have had the syndrome for four or more days. Some task force members felt that any duration of this syndromal criteria should be sufficient. However, most responders (75%) thought that ultra-short episodes have many possible explanations, and some limit should be imposed. Of those nominating a finite period, the modal recommendation was two days for both mania and hypomania.

Thus, for patients who have a sufficient number of symptoms to meet criteria, it may be that [hypo]mania durations of as little as two days could be a reasonable basis for concluding that the diagnosis is probably bipolar disorder and treatments should be chosen accordingly.

The group also came up with a new proposed definition for hypomania and mania:

A distinct period of either an abnormally elevated and expansive mood, or an irritable and quick-tempered mood, characterized by increased activity and cognition such that the individual feels unusually energized, hyper, or wired. Such changes are perceived at the time or on later reflection as excessive and an unambiguous change in functioning from the individual’s usual state.

The consensus was that this characterized the disorder better than the current DSM definition.

In differentiating bipolar I from bipolar II, the majority voted to continue to require marked disturbance in functioning at work or socially for bipolar I (mania). However, the requirement that hospitalization would automatically qualify the patient for bipolar I was strongly opposed. This requirement was considered arbitrary and too dependent on local health services practices, insurance, or other external factors. However, if the patient was hospitalized, that certainly could be an indicator of severity and likely mania. The group thought psychosis should be retained as a criterion indicating mania.

The group has studies underway to test these proposed changes and others to see how well they describe a consecutive series of patients in clinical practice. They are also looking at 78 possible symptoms of mania to see if any are better than the seven in DSM-5.

Dr Osser is Associate Professor of Psychiatry, Harvard Medical School, and Consulting Psychiatrist, US Department of Veterans Affairs, National Telemental Health Center, Bipolar Disorders Telehealth Program, Brockton, MA. He reports no conflicts of interest concerning the subject matter of this article.

1. Parker G, Tavella G, Macqueen G, et al. Revising DSM-5 criteria for the bipolar disorders: Phase 1 of the AREDOC project. 

Bipolar II Disorder: Modelling, Measuring, and Managing

, 3rd ed. New York, NY: Cambridge University Press; 2019

An international task force of experts in the diagnosis and treatment of bipolar disorder was recently convened to address concerns about DSM-5 criteria, particularly the definitions of manic episodes. The DSM’s duration criteria is an area of concern.

Mania and Hypomania: The Latest Thinking on Duration of Episodes and Other Features

In the past several years at the VA National Tele-Bipolar Disorder Expert Consultation Program, my colleagues Drs Eric Smith, Laszlo Gyulai, and I have been writing monthly educational newsletters for clinicians (nationwide) who have been requesting telemedicine consultation on diagnostic and treatment problems of patients with bipolar disorder or possible bipolar disorder.

 Over 2500 consultation requests have been received over more than 8 years and 2100 consultation notes have been delivered, so our group has developed considerable experience with this challenging disorder and the wide variety and complexity of the clinical scenarios and comorbidities that are encountered.

The newsletters are designed for easy and quick reading: all are one typed page in length, with one to three reference citations. The Editor and Board of 

 learned of these newsletters and requested to have them published (after review) and made available to their readership. The first one can be read 

. The content of these newsletters does not reflect the position of the Department of Veterans Affairs and is solely the product of the authors.

As the coordinator of these publications, I should introduce myself. I have an appointment as Associate Professor of Psychiatry at Harvard Medical School at the VA Boston Healthcare System, Brockton Division. My area of clinical and academic expertise is in the development of evidence-derived algorithms for the psychopharmacology of psychiatric disorders, an endeavor I have been dedicated to since 1985. These algorithms have been published and republished in updated versions and (since 1995) converted to web-based applications that enable rapid and international access to the recommendations through the (free) website of the Psychopharmacology Algorithm Project at the Harvard South Shore Residency Training Program (psychopharm.mobi).

Dr Robert Patterson, a psychiatrist affiliated with McLean Hospital, created the technology for translating the algorithms into their web versions. 

 has published articles over the years about the algorithms.

 There are algorithms for 10 disorders. There is no commercial activity associated with the website nor have we received any funding for our work from pharmaceutical firms or others: it has been a labor of love for Dr Patterson and me and about 25 collaborators on the different algorithms. It was a great privilege in 2011 to be offered the opportunity to do these consultations and see these complex patients and refine my thinking about their needs and the optimal application of the evidence-base to their care.

To introduce the columns, I begin with a few brief comments about the challenges of diagnosing bipolar disorder. On this, the evidence is clear: the condition is frequently both underdiagnosed and overdiagnosed.

 Patients having manic episodes may be functioning fairly well (or, as they see it, very well indeed) when manic and may not recognize or want to acknowledge the abnormal mood state, and may not seek care. Erroneous diagnoses and incorrect treatment can continue for many years.

The rate of suicide in bipolar disorder is quite high. Hence, the most important initial advice we can give readers of this column is to please pull out your DSM-5 and review the criteria for mania and hypomania. Take the time to carefully assess the patient using these criteria, looking particularly for a history of discreet episodes lasting at least 3 to 4 days. It can help to have a significant other who knows the patient well give input as to whether these discreet episodes have been occurring. Avoid making a positive diagnosis of mania or hypomania after hearing about or observing just a couple of symptoms (eg, racing thoughts, rapid speech, tangential speech). Quick diagnosis on a hunch is a very error-prone process with bipolar disorder. Patients with rapid or overly productive speech and thoughts could have ADHD, PTSD, substance use disorders, or other problems-or all of them at once. If so, each needs to be treated separately-prioritized in order of importance.

 readers. There will be some surprises coming in future issues!

Dr Osser is a Consulting Psychiatrist, US Department of Veterans Affairs, National Telemental Health Center, Bipolar Disorders Telehealth Program, Brockton, MA.

 Bauer MS, Krawczyk L, Tuozzo K, et al. Implementing and sustaining team-based telecare for bipolar disorder: lessons learned from a model-guided, mixed methods analysis. 

 Osser DN, Patterson RD. Enhancing clinical decision-making. 

 Osser DN. The role of guidelines and algorithms for psychopharmacology in 2007. 

 McIntyre RS, Zimmerman M, Goldberg JF, First MB. Differential diagnosis of major depressive disorder versus bipolar disorder: current status and best clinical practices. 

The evidence is clear: bipolar disorder is frequently both underdiagnosed and overdiagnosed.

Fasten Your Seatbelts

Current estimates are that 4% to 5% of the population is at risk for a disorder on the bipolar spectrum. Among the patients in the so-called soft portion of that spectrum are those with a disturbance of temperament in the direction of hypomania.

The concept of temperament is a product of German nosological research from a century ago starting with Kraepelin. In the US, the concept has been championed by Hagop Akiskal, MD and his colleagues. Akiskal is now the editor emeritus of the 

. The notion of depressive temperament has been incorporated into DSM-5 nosology in the form of “persistent depressive disorder” (previously called dysthymia). The other pole was called hyperthymia by the Germans. DSM committees have considered adding hyperthymia but have not done so. The research base on it is still, to many, unconvincing. However, it seems that in clinical practice one encounters individuals who have chronic low-grade hypomanic symptoms-high energy, need for less sleep than others, chronic optimism, chronic risk taking. These individuals can be prone to major depressions and can become severely suicidal.

Akiskal and colleagues have been describing these patients for almost 40 years. Their research criteria for hyperthymic temperament include onset before age 21, habitual sleep of less than 6 hours even on weekends, excessive use of denial, and traits (described originally by Schneider et al) that include being overoptimistic, self-assured, grandiose, overtalkative, warm and people-seeking, uninhibited, promiscuous, and meddlesome.

 Neurobiological studies have suggested the individuals have dopaminergic dysregulation.

Treatment issues have focused on what medications to use when hyperthymic individuals become depressed. The studies have all been uncontrolled. However, it seems that antidepressants are ineffective for these depressions and often trigger a mixed state or frank mania at times. Mood stabilizers and medications effective for bipolar depression may be more appropriate for the depressions in these patients.Usually their sunny temperament itself doesn’t require treatment and may, in fact, foster excellent productivity and creativity during much of their lifespan.

 Akiskal HS, Mallya G. Criteria for the “soft” bipolar spectrum: treatment implications. 

 Rihmer Z, Akiskal KK, Rihmer A, Akiskal HS. Current research on affective temperaments. 

Current estimates are that 4% to 5% of the population is at risk for a disorder on the bipolar spectrum. Among the patients of that spectrum are those with a disturbance of temperament in the direction of hypomania.

Author | David N. Osser, MD

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