David N. Osser, MD

To read more about these algorithms, see 

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 is a member of

Editorial Board. The author reports no conflicts of interest concerning the subject matter of this article.

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Dr Osser discusses 4 new algorithms to help improve your practice. 

4 New Algorithms to Help Improve Practice

Do you think of duloxetine when your patient with depression (bipolar or otherwise) reports chronic pain? The psychiatric prescribing clinician may be called upon to prescribe medication for the pain or may be asked by the primary care clinician or pain clinic if certain pain medications would be acceptable considering bipolar comorbidity. Or, those clinicians may go ahead and prescribe duloxetine or amitriptyline without even notifying you.

 discussed that antidepressants, especially serotonin-norepinephrine reuptake inhibitors (SSRIs) and tricyclics, are generally ill-advised for patients with bipolar disorder because of the risks of increasing cycling, especially to depression and, over the long term, to 

Although some antidepressants (eg, duloxetine) are approved by the US Food and Drug Administration for use in pain syndromes like fibromyalgia, diabetic neuropathy, and chronic musculoskeletal pain, it is also important to recognize the evidence shows they are minimally effective in addressing pain in patients with depression. The great majority of patients in studies of these pain conditions were not depressed. Four meta-analyses reviewed by 

 have evaluated the effect of antidepressants on pain in patients with depression. The effect size of antidepressants versus placebo on comorbid pain in patients with depression is very small and usually clinically insignificant, regardless of the antidepressant used. Duloxetine, notably, did not stand out as any more effective than the others (tricyclics, paroxetine, venlafaxine, other SSRIs). We are talking about duloxetine reducing pain by 12% to 27% more than placebo reduced it—a difference that does not seem meaningful.

Duloxetine was extensively marketed based upon its FDA indications for pain management treatment and became a multi-billion-dollar product (until its patent expired and it became generic), but review authors concluded that this economic activity was not justified by the evidence. There is no reason to think of it as the go-to medication for a depressed patient with pain difficulties. Further, a Cochrane review of depression studies found that the dropout rate with duloxetine was higher than with escitalopram or venlafaxine, possibly due to greater adverse effects.

 If the patient is not depressed and has these pain syndromes, duloxetine may play a role. The meta-analyses did find a correlation between improvement in depression and improvement in pain.

 This suggests that choosing medications (unlike duloxetine) that work in bipolar depression (eg, FDA-approved options) may result in some improvement in pain.

Cannabis is being considered for treatment of pain as an alternative to opioids.

 the significant evidence that cannabis causes more cycling and destabilization in patients with bipolar disorder, and that it is without an evidence-base for pain.

 It is, therefore, irresponsible to encourage patients with severe pain and opiate misuse problems to consider cannabis as a viable treatment.

Medications with reasonable evidence of modest efficacy for pain that do not exacerbate symptoms of bipolar disorder include acetaminophen; non-steroidal anti-inflammatory agents (stronger than acetaminophen—but be careful about the interaction with lithium to raise lithium levels); gabapentin (no efficacy for mood swings, though); pregabalin (may work when gabapentin fails, possibly because of genetically based transporter-related interactions); and carbamazepine (for trigeminal neuralgia and possibly other kinds of pain). It should be stressed that there are many non-pharmacological strategies for pain management, such as mindfulness training, physical activity and therapy, massage, and acupuncture (

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 is a member of the 

 Editorial Board. The author reports no conflicts of interest concerning the subject matter of this article.

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

2. McGirr A, Vöhringer PA, Ghaemi SN, et al. Safety and efficacy of adjunctive second-generation antidepressant therapy with a mood stabilizer or an atypical antipsychotic in acute bipolar depression: a systematic review and meta-analysis of randomized placebo-controlled trials. 

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

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

4. Gebhardt S, Heinzel-Gutenbrunner M, König U. 

Pain relief in depressive disorders: a meta-analysis of the effects of antidepressants

5. Cipriani A, Koesters M, Furukawa TA, et al. Duloxetine versus other anti-depressive agents for depression. 

6. Humphreys K, Saitz R. Should physicians recommend replacing opioids with cannabis? 

Cannabis: Patients With Bipolar Should Avoid Use.

Articles

The psychiatric prescribing clinician may be called upon to treat pain comorbid with bipolar disorder.

Addressing Pain in Patients With Bipolar Disorder

 found that children diagnosed with attention deficit/hyperactivity disorder (ADHD) had a 10-fold increase in the incidence of later development of bipolar disorder compared with matched children without ADHD.

, has a more severe course than either diagnosis alone, and is associated with greater risk of suicide attempts.

 Clinicians will have trouble determining which diagnosis best fits the patient, and it actually could be that the patient has both. Often the patient (and/or prescriber) prefers the ADHD diagnosis and the stimulant medications used to treat it. They hope to avoid the diagnosis of bipolar disorder and medications used to treat it, because of the perceived stigma and complexity of treatment. The differential diagnosis is made by recognizing that bipolar (hypo)manias occur in discreet episodes of at least 4 to 7 days, whereas the hyperactivity and associated symptoms of ADHD are more or less constantly present as features of the individual’s temperament.

The comorbidity of ADHD and bipolar may involve overlapping genetics. In Sweden, 13,532 twin pairs (aged 9 to 12 years) were evaluated using parent-rated instruments for 

 Overlapping symptoms were removed to aid in the analysis. The twin pairs were reassessed at age 15 and again (n=3013) at age 18. They found that genetic factors associated with hypomania explained 25% to 42% of likelihood of having ADHD’s hyperactive/impulsive symptoms. There was less effect on the inattentive symptoms of ADHD. Monozygotic twins had a stronger association of the 2 conditions than the dizygotic twins. The rest of the variance was presumed to be associated with causes of ADHD that do not contribute to causing hypomania.

The bottom line of these data is that it is important to take the time to diagnose bipolar accurately in patients with a history of ADHD or presenting with current ADHD. Mood stabilizing medications such as lithium will usually be indicated for the bipolar condition.

Stimulant treatment of ADHD when there is comorbid bipolar has been controversial. However, 

 was published in 2016 by Viktorin and colleagues

 that may influence practice. This large observational study found that if patients are treated with methylphenidate for ADHD, and their bipolar disorder is not being treated with a mood stabilizer, the likelihood of manic switch over 3 to 6 months is increased by nearly 7-fold, compared with patients with bipolar disorder not treated with methylphenidate. However, if patients are on a bipolar mood stabilizer, the addition of methylphenidate was associated with 

 odds of becoming manic, compared with the control patients with bipolar disorder not given a stimulant, with a hazard ratio of 0.6 (ie, a 40% reduction). Thus, it seemed that methylphenidate can be safe and effective for ADHD symptoms if the patient is on a mood stabilizer to manage the bipolar disorder. Note that amphetamine products were not evaluated in this Scandinavian study: many European countries have not approved them.

In summary, it is critically important to carefully evaluate whether patients with ADHD also have bipolar disorder. If you miss the bipolar diagnosis and treat the ADHD with a stimulant, the potential for harm (induction of mania) is considerable. However, if the bipolar disorder is under control with a mood stabilizer, the use of a stimulant (at least methylphenidate) need not be avoided. Indeed, it may be quite helpful.

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

1. Meier SM, Pavlova B, Dalsgaard S, et al. Attention-deficit hyperactivity disorder and anxiety disorders as precursors of bipolar disorder onset in adulthood. 

2. Lan WH, Bai YM, Hsu JW, et al. Comorbidity of ADHD and suicide attempts among adolescents and young adults with bipolar disorder: a nationwide longitudinal study. 

3. Hosang GM, Lichtenstein P, Ronald A, et al. Association of genetic and environmental risks for attention-deficit/hyperactivity disorder with hypomanic symptoms in youths. 

4. Viktorin A, Rydén E, Thase ME, et al. The risk of treatment-emergent mania with methylphenidate in bipolar disorder. 

Although clinicians and patients may wish otherwise, the comorbidity of ADHD and bipolar disorder needs to be considered.  

ADHD in Bipolar Patients: Genetics, Diagnosis, and Treatment

Valproic Acid: Overused in Bipolar Disorder?

Giving Valproic Acid a Higher Priority in Bipolar Patients

I am pleased to be offered the opportunity to respond to the 

commentary by Bernardo Dell’Osso, Monica Macellaro, and Terence A. Ketter

. I appreciate that these distinguished clinicians and scientists have taken an interest in this piece, especially because they largely agree with most of the points made, adding some validity to the perspectives presented.

They begin by proposing, without citing evidence, that valproate does not deserve a low priority in some subgroups of bipolar patients. They affirm that it can be reasonable for male and female patients not of child-bearing potential, especially the “very young” (presumably younger than the children and adolescents in the Wagner et al study

, in which valproate did not do better than placebo), and elderly females. They did agree that valproate had inferior results compared with most other competing antimanic medicines in the 3 meta-analyses cited. I can add the more recently published GERI-BD study involving 224 elderly inpatients (with equal numbers of men and women) that found, consistent with the meta-analyses, lithium to be superior to valproate for acute mania over 9 weeks and comparably tolerated.

The commentators then proposed that I failed to note contraceptives could mitigate the teratogenicity and related risks to offspring exposed to valproate. However, they fail to note that 50% of pregnancies are unplanned. Thus, it seems difficult to be confident in contraceptive adherence (especially should a hypomania or mania occur). Combining that consideration with the marginal efficacy in the evidence base and the very high risk of fetal harm, valproate still seems to be nearly the lowest priority option for women of child-bearing potential. Use of valproate in this population is considered to be a major public health problem in Europe.

The commentators next raise the possibility of “methodological limitations,” explaining the negative controlled studies of valproate in acute mania without describing them. The authors of the negative Hirschfeld et al study

 of valproate proposed that failure could have been due to their use of what they termed a “moderate” mean dose of 2200 mg daily. In the previous, only modestly positive study

, participants received a mean dose of 3350 mg daily. However, there were more side effects of somnolence, nausea, vomiting, and dizziness in that study. Few clinicians use such a high dose. Also, the authors noted that the protocol of the negative study encouraged earlier hospital discharge, which may have made it more difficult to find a difference from placebo. The negative study also allowed longer use of adjunctive lorazepam, which may have added support to the placebo group. However, shorter hospital stays are the standard today, and experts encourage liberal use of adjunctive benzodiazepines in treating mania.

 Thus, the conditions that may have resulted in valproate not being found efficacious in its most recent study are likely to be present in usual practice today.

The commentary discussed the lack of FDA-approval for valproate as a maintenance treatment. The cited maintenance study that failed to show efficacy indeed had faults—and one that is often mentioned is that the lithium group had more suicidal issues than the placebo group, contrary to most other evidence, suggesting that there was something peculiar about the patient sample. The commentators encouraged not making too much of FDA-approval as a basis for decision-making. They noted that the FDA has approved adding medications like second generation antipsychotics (SGA) to mood stabilizers including valproate and lithium. However, these SGAs are also efficacious and approved as monotherapies for mania, and in the design of all these enhancement studies, the patient must first have been on the valproate or lithium for 2 weeks and not responded before the SGA or placebo is added. So, these studies do not contribute to the evidence base for the efficacy of valproate: the improvement could have been entirely from the SGA. Other studies including the BALANCE 2-year trial of lithium versus valproate versus the combination found valproate far less effective than lithium.

 Effectiveness as a maintenance treatment should be an important consideration in choosing a medication for an acute episode. 

After some remarks in agreement with the article, the commentary discusses the relative weight gain from valproate versus olanzapine. The authors assert that even if valproate causes more weight gain than olanzapine in head-to-head trials, olanzapine is more widely avoided. This is likely true. Probably both should be avoided in favor of other agents for mania at least for first-line use, as asserted in important national and international guidelines.

Next, there is mention of the relative benefit or harm from valproate versus lithium in patients with suicidal tendencies. There is nothing of importance in the literature to suggest that valproate has any benefit for this common problem in patients with bipolar disorder, even if, as the commentary authors assert, the FDA’s suicide risk warning on valproate was not based on strong evidence.

On the other hand, I agree with the importance of mentioning that carbamazepine, which may have a larger effect size for efficacy in acute mania, has almost as many problems for women of child-bearing potential. It also carries the same suicide risk warning that the FDA required for anticonvulsants.

In the final remarks, the commentary reiterated and added evidence that valproate is being very widely used especially in the United States, but that agreed that lithium, SGAs, lamotrigine, and carbamazepine should figure prominently in selecting medication for bipolar patients. The purpose of my article was, indeed, to urge clinicians to reappraise their preference for valproate. 

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, MA. 

1. Wagner KD, Redden L, Kowatch RA, et al. A double-blind, randomized, placebo-controlled trial of divalproex extended-release in the treatment of bipolar disorder in children and adolescents. 

2. 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. 

3. Sher J, Frank JW, Doi L, de Caestecker. Failures in reproductive health policy; overcoming the consequences and causes of inaction. 

4. Hirschfeld RM, Bowden CL, Vigna NV, Wozniak P, Collins M. A randomized, placebo-controlled, multicenter study of divalproex sodium extended-release in the acute treatment of mania. 

5. Bowden CL, Swann AC, Calabrese JR, et al. A randomized, placebo-controlled, multicenter study of divalproex sodium extended release in the treatment of acute mania. 

6. Mohammad O, Osser DN. The psychopharmacology algorithm project at the Harvard South Shore Program: an algorithm for acute mania. 

7. Geddes JR, Goodwin GM, Rendell J, et al. Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial. 

8. Kessing LV, Hellmund G, Geddes JR, Goodwin GM, Andersen PK. Valproate v. lithium in the treatment of bipolar disorder in clinical practice: observational nationwide register-based cohort study. 

David Osser, MD, comments on the low priority of valproate for treating patients with bipolar disorder. 

Reappraising a Preference for Valproate

Oxcarbazepine (formerly branded as Trileptal) is an anticonvulsant that is structurally very similar to carbamazepine, which is US Food and Drug Administration-approved for acute or mixed mania but not well studied for depression. Both are thought to work by the same mechanism(s). The drug came to market as an anticonvulsant with very little time left on its patent protection, and it very quickly became a generic product. There was not enough time to do any significant studies on other possible uses such as in bipolar disorder before the patent ran out. Hence, there are very little data pertinent to its efficacy or effectiveness for bipolar mania or depression. What data are available are at best inconclusive,

 citing 8 pertinent reports, rate it as “probably effective” for mania—the only medication with that rating in a table of 13 off-label possible alternative treatments.

The only placebo-controlled study was in children and adolescents.

 The study included a total of 116 patients with symptoms of mania aged 7 to 18 years who were randomized to oxcarbazepine or placebo. There was no significant difference on the Young Mania Rating Scale, nor on rate of response defined as a 50% improvement in the scores. However, the response rates were 42% with oxcarbazepine and 26% with placebo, which looks like it could have become a significant difference if the cohort had been larger.

Oxcarbazepine has a somewhat milder adverse effect profile compared with carbamazepine. Probably the most significant risk with oxcarbazepine is 

; this most often occurs in the first 3 months of use, but it can occur later. Although few head-to-head comparisons are available,

 the incidence might be higher in oxcarbazepine than with carbamazepine. The overall rate is about 2% to 3%, but concomitant selective serotonin reuptake inhibitors (which can lower sodium by a different mechanism) probably increase this risk. Sodium monitoring should occur monthly for the first 3 months and every 3 to 6 months thereafter.

Adverse effects that appear less often with oxcarbazepine include liver enzyme elevations (it is not metabolized and is renally excreted), serious rashes including Stevens-Johnson syndrome, leucopenia, sedation, and other rashes. It is a weaker inducer of cytochrome P450 3A4 compared with carbamazepine and thus has fewer drug interactions. Both oxcarbazepine and carbamazepine are weight-neutral, but they can cause double vision and vertigo. Slower titration may minimize these and other adverse effects. Teratogenicity is a severe problem with carbamazepine; the incidence is unclear with oxcarbazepine but it probably should be considered to be an equally high risk in women of child-bearing potential.

Dosage of oxcarbazepine is about one-third higher than with carbamazepine. The same dose has been used for bipolar mania as is used for seizure disorders; begin with 300 mg bid and increase every 3 days by 300 mg to the maximum dose of 2400 mg, if needed and tolerated. Serum levels are not available.

In conclusion, it seems that oxcarbazepine could be a consideration for patients who you want to treat with carbamazepine for mania (as monotherapy or adjunct) but for whom it would be unsafe or who have been unable to tolerate it. It is unlikely to be of value for someone who had an adequate trial of carbamazepine and has not responded. The evidence base for treating or preventing bipolar depression is very weak for both.

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 is a member of 

1. Vasudev A, Macritchie K, Vasudev K, et al. Oxcarbazepine for acute affective episodes in bipolar disorder. 

The Maudsley Prescribing Guidelines in Psychiatry

13th Edition. Hoboken, NJ: Wiley Blackwell; 2018: 237.

3. Wagner KD, Kowatch RA, Emslie GJ,et al. A double-blind, randomized, placebo-controlled trial of oxcarbazepine in the treatment of bipolar disorder in children and adolescents. 

Oxcarbazepine might be considered for patients who you want to treat with carbamazepine for mania (as monotherapy or adjunct) but for whom it would be unsafe or who have been unable to tolerate it. 

Oxcarbazepine: Does It Have a Role in Bipolar Disorder?

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.

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. 

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. 

Do you need help persuading patients to try lithium?