David N. Osser, MD

Prazosin: The Best Medication for Comorbid PTSD? 

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Why does prazosin appear to be the safest and most effective medication for select patients with comorbid PTSD? 

 (PTSD) is often found to be a comorbidity in patients with bipolar disorder. In fact, sometimes it is the primary problem.

Irritable mood is a regular feature of PTSD. Triggers include events or thoughts related to the original trauma, which elicit an immediate adrenalized fight-or-flight response. Patients with PTSD will almost always 

 with sleep disturbance, including nightmares, disturbed awakenings without nightmare recollection, and night terrors observed by bed partners but not remembered.

 Although mania can present with irritable (rather than elevated) mood during manic episodes, the irritability in mania tends to occur when others disagree with the unrealistic plans or problematic behaviors of the individual with mania. In DSM-5 mania, the patient must present with 4 rather than 3 of the additional [hypo]manic symptoms during manic episodes if the mood is irritable.

The best medication for PTSD-related sleep disturbances, and perhaps other symptoms as well, is prazosin, which is an α-1 adrenergic antagonist antihypertensive agent. There have been 9 randomized, placebo-controlled trials of prazosin for PTSD, 6 of which have reported positive results. Some of these study 

 were strongly positive, with effect sizes compared with placebo in the neighborhood of 1.0 for all symptoms.

, which was published in 2018 and included 304 veterans from 13 medical centers, found no efficacy with prazosin.

 Doses were raised over 5 weeks, to up to 20 mg in men and 12 mg in women (higher than previous studies for the women). Some guidelines (including the latest Veterans Affairs PTSD practice guidelines) concluded that the medication had little value. The authors and others tried to explain these negative results, noting issues such as clinicians’ reluctance to refer very distressed and unstable patients to the study. If patients were receiving trazodone, they could not participate unless they were willing to stop taking it. Trazodone helps many patients with PTSD fall asleep, even if it has not demonstrated efficacy for staying asleep and preventing 

. Prazosin (a nonsedative), on the other hand, is not particularly helpful for initial insomnia. Prazosin had also been prescribed in study hospitals for many years, and perhaps the best patient candidates had already been treated.

This study made it clear that there are many patients who do not respond to prazosin and that research is needed to determine whether there are predictors of response.

Already we know that high blood pressure, which is a common medical comorbidity in PTSD, is a predictor.

 Raskind has termed these patients the “adrenergic subtype” of PTSD. In their 2013 study,

 which reported positive results overall, the authors found that patients with a baseline systolic blood pressure of 110 mm Hg or less did not respond to prazosin better than to placebo.

 Benefits rose sharply with each increase of baseline systolic blood pressure of 10 mm Hg.

Another predictor of poor response could be active drinking in patients who have an alcohol use disorder (AUD) and are actively drinking. Results of a 

 (N = 96) with comorbid AUD who were actively drinking during treatment with prazosin showed no efficacy for sleep or other PTSD symptoms. In another negative study, veterans (N= 20) with nightmares and mild to moderate suicidal ideation were given prazosin at night.

 Nightmares improved more with placebo than with prazosin, and there was no difference in suicidal ideation or daytime PTSD symptoms. Thus, it may be that suicidal ideation predicts poor response; a larger study is needed to better understand this link. Notably, among the 3 trials reporting negative results for prazosin, the only positive finding for prazosin was a lower rate of suicidal ideation in the prazosin group (8%) compared with placebo (15%) in the large 2018 study.

 However, this was a secondary outcome measure.

In an 8-week study comparing prazosin, hydroxyzine, and placebo in 100 patients with 

 associated with PTSD (28% women), investigators found prazosin was superior to both hydroxyzine and placebo in reducing nightmares and improving other measures of sleep quality.

 Hydroxyzine was also more effective than placebo on these measures in this study, which is the only controlled study of hydroxyzine in PTSD to date.

In conclusion, prazosin appears to be effective and perhaps the best medication for properly selected patients with PTSD, especially for their sleep disturbances. It might also address daytime symptoms, including irritability. Prazosin generally does not interact with medications for bipolar disorder. It is not particularly sedating, so another medication is often 

 to address initial insomnia. Hydroxyzine and trazodone are good options.

 Clinicians should be aware that there is a rare risk of priapism with prazosin, so, theoretically, there may be a greater than usual risk when combining trazodone and prazosin. Patients should be warned to pay attention to this possible side effect.

The effective doses of prazosin (after slow titration over several weeks) in the studies supporting its use clustered around a mean of 15 mg at bedtime for men and about half that for women. However, patient sensitivity to the medication is 

, with some patients only needing 1 mg and some needing and tolerating more than 20 mg.

 The highest dose mentioned in the literature was 45 mg at bedtime in a case report.

is associate professor of psychiatry, Harvard Medical School, and colead psychiatrist at the US Department of Veterans Affairs, National Telemental Health Center, Bipolar Disorders Telehealth Program, Brockton, Massachusetts. He also serves as a member of the Editorial Board of

. Dr Osser has no financial disclosures regarding this article

The Psychopharmacology Algorithm Project at the Harvard South Shore Program: an update on posttraumatic stress disorder

2. Germain A, Richardson R, Moul DE, et al. 

Placebo-controlled comparison of prazosin and cognitive-behavioral treatments for sleep disturbances in US military veterans

3. 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. 

4. Ahmadpanah M, Sabzeiee P, Hosseini SM, et al. Comparing the effect of prazosin and hydroxyzine on sleep quality in patients suffering from posttraumatic stress disorder. 

5. Raskind MA, Peskind ER, Chow B, et al.

 Trial of prazosin for post-traumatic stress disorder in military veterans

6. Raskind MA, Millard SP, Petrie EC, et al. Higher pretreatment blood pressure is associated with greater posttraumatic stress disorder symptom reduction in soldiers treated with prazosin. 

7. Petrakis IL, Desai N, Gueorguieva R, et al. 

Prazosin for veterans with posttraumatic stress disorder and comorbid alcohol dependence: a clinical trial

8. McCall WV, Pillai A, Case D, et al. A pilot, randomized clinical trial of bedtime doses of prazosin versus placebo in suicidal posttraumatic stress disorder patients with nightmares. 

9. Koola MM, Varghese SP, Fawcett JA. High-dose prazosin for the treatment of post-traumatic stress disorder. 

Articles

Prazosin appears to be effective and perhaps the best medication for selected patients, including those with bipolar disorder.

Comorbid PTSD: Update on the Role of Prazosin

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?

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

Recent study results revealed that children with a diagnosis of attention-deficit/hyperactivity disorder (ADHD) had a 

 in the incidence of later development of bipolar disorder (BD) compared with matched children without ADHD.

 is common, 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 could be that the patient has both diagnoses. Often the patient (and/or prescriber) prefers the ADHD diagnosis and the stimulant medications used to treat it. They hope to avoid the BD diagnosis 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 discrete 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 BD may involve overlapping genetics. In Sweden, 13,532 twin pairs (aged 9 to 12 years) were 

 using parent-rated instruments for ADHD and hypomanic episodes.

 Overlapping symptoms were removed to aid in the analysis. The twin pairs were reassessed when aged 15 years and again when aged 18 years (N = 3013 pairs). They found that genetic factors associated with hypomania explained 25% to 42% of the likelihood of 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 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 disorder accurately in patients with a history of ADHD or who are 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 BD has been controversial. However, an important 2016 study by 

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

 not treated with methylphenidate. However, if patients are on a bipolar mood stabilizer, the addition of methylphenidate was associated with reduced odds of becoming manic, compared with the control patients with BD who were 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 BD. Note that amphetamine products were not evaluated in this Scandinavian study; many European countries have not approved these agents.

In summary, it is critically important to carefully evaluate whether patients with ADHD also have BD. If you miss the bipolar diagnosis and treat the ADHD with a stimulant, the potential for harm (ie, 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 the 

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

This article was originally posted ahead of print on October 30, 2020 under the title ADHD in Bipolar Patients: Genetics, Diagnosis, and Treatment, and has since been updated. -Ed

1. Meier SM, Pavlova B, Dalsgaard S, et al. 

Attention-deficit hyperactivity disorder and anxiety disorders as precursors of bipolar disorder onset in adulthood

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, Lundström, Taylor MJ. 

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 Patients With Bipolar Disorder: Genetics, Diagnosis, and Treatment

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.

Videos

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 

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.

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

Addressing Pain in Patients With Bipolar Disorder

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. 