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7 Questions that Separate ADHD from Bipolar Disorder

What are they key differences between ADHD and bipolar disorder? How can they be identified? 

Bipolar disorder is associated with overactive protein kinase C (PKC) intracellular signaling.

 that approved treatments for bipolar disorder, including lithium and valproate, are PKC inhibitors.

 There is also evidence that tamoxifen, which is approved for breast cancer prevention and treatment, is a central nervous system PKC inhibitor.

 The active metabolite of tamoxifen, endoxifen (4-OH-N-Desmethylfamoxifen) is a 4-fold greater PKC inhibitor than tamoxifen and showed evidence for efficacy in patients with bipolar mania in a Phase II trial.

 performed a Phase III double-blind, active-controlled study of endoxifen in patients with bipolar I disorder. The trial was performed at 18 study centers in India. The study consisted of a 1-week screening phase (with a 2-day drug-free observation phase prior to randomization), a 3-week double-blind treatment phase in the hospital setting, and a 2-week post-treatment follow-up phase.

Study authors randomized 228 adult inpatients aged 18 to 65 years with DSM-V5 bipolar I disorder experiencing a current manic episode (with or without mixed features). Patients had a Young Mania Rating Scale (YMRS) ≥ 20 (and ≥ 4 on 2 of 4 core items—irritability, speech, content, disruptive/aggressive behavior), a Clinical Global Impression (CGI) score of ≥ 4, and a history of response to previous treatment with lithium, valproate, carbamazepine, or non-clozapine antipsychotics. Exclusion criteria were history of seizures, 

, retinal vein thrombosis, hypersensitivity/intolerance to tamoxifen/endoxifen, no previous treatment for bipolar disorder, and ≥ 20% improvement in YMRS score between screening and randomization.

Participants were randomized 1:1 to enteric-coated 8 mg endoixfen or 1000 mg extended-release divalproex sodium once daily. Concomitant benzodiazepines were allowed for acute agitation or akathisia, but avoided within 12 hours of scheduled mania ratings. Risperidone/haloperidol were allowed as “rescue medication” for symptomatic worsening or agitation, but if required, those patients were discontinued from the study. The primary study endpoint was change in the YMRS from baseline to day 21. Efficacy was analyzed in a modified intent-to-treat in patients who received at least 1 dose and had at least 1 efficacy evaluation, using a last-observation-carried-forward approach. The least square mean change in YMRS was evaluated using analysis of covariance.

A total of 276 patients were screened and 228 were included in the study (endoxifen n = 116, divalproex n = 112). Mean age was 35, and 70% of patients were male. All patients administered benzodiazepines were from 1 site, none of whom were withdrawn.None of the patients required rescue medications. Endoxifen demonstrated a significant, 15.2-point reduction in mean YMRS at day 21 (33.1 to 17.8), as well as reduction in the Montgomery-Åsberg Depression Rating Scale score, with a similar effect observed in the divalproex group. Most adverse events in the endoxifen group were mild-moderate, most commonly headache (8%), vomiting, insomnia, and restlessness. Endoxifen was associated with significant increases in total, LDL, and HDL cholesterol, but no significant changes in blood platelets.

The authors concluded that endoxifen was effective and generally well tolerated in the treatment of acute manic or mixed episodes in the context of bipolar I disorder. They noted that improvements in YMRS score were similar to the previous Phase II study.

Potential advantages of endoxifen are that it crosses the blood brain barrier and is independent of CYP2D6 metabolism. Limitations of the trial include the short study duration (21 days) and absence of data on blood divalproex levels.

Endoxifen is a potential new treatment option for acute mania in patients with 

 that showed similar clinical efficacy as divalproex, without evidence of risk of thrombocytopenia. In contrast to valproate and lithium, another potential advantage of endoxifen is that therapeutic drug monitoring is not required due to a wide therapeutic index.

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

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

1. Saxena A, Scaini G, et al. Role of Protein Kinase C in Bipolar Disorder: A Review of the Current Literature. 

Protein kinase C inhibitors: rationale for use and potential in the treatment of bipolar disorder.

3. Zarate CA, Singh JB, Carlson PJ, et al. Efficacy of a protein kinase C inhibitor (tamoxifen) in the treatment of acute mania: a pilot study. 

4. Yildiz A, Guleryuz S, Ankerst DP, et al. Protein kinase C inhibition in the treatment of mania:

a double-blind, placebo-controlled trial of tamoxifen. 

5. Ahmad A, Sheikh S, Shah T, et al. Endoxifen, a New Treatment Option for Mania: A Double-Blind, Active-Controlled Trial Demonstrates the Antimanic Efficacy of Endoxifen. 

6. Ahmad A, Sheikh S, Ali Khan M, et al. Endoxifen: 

A New, Protein Kinase C inhibitor to treat acute and mixed mania associated with bipolar I disorder

Protein Kinase C Inhibitors in the Treatment of Bipolar Mania

A single sentence in the landmark textbook 

by Frederick Goodwin, MD, and Kay Jamison, PhD, overshadows much of the progress we have made in treating bipolar disorder: “Complete symptomatic remission does not ensure functional recovery.”

 In other words, we can treat the symptoms but that does not mean our patients will get their lives back. Strained marriages, checkered work histories, and lost friendships become the norm.

For these patients, it is not the depression or the mania but the cognitive symptoms of bipolar disorder that get in the way. Memory, attention, and higher-order constructs like judgment and social intuition are among the impairments that can persist after symptomatic remission, and they do so in about 30% to 60% of cases. Compared to mood symptoms, cognitive problems are more difficult to treat, but they can be helped.

The first step is recognition. Clinicians should ask questions such as: “Now that the depression and mania have gone away, do you feel like your mind is working fully, or are there still areas of life where you are not functioning all the way?” From there, assess occupational functioning (eg, finishing tasks, prioritizing, and time management) and household chores (eg, bills, shopping, cleaning, and basic hygiene). Also inquire about hobbies and recreation as well as family, relationship/sexual, and social life (eg, have they lost interest, has enjoyment faded, can they follow a plot of a movie, are there problems in relationships?).

Although subjective assessments are important and provide information about quality of life, objective testing can also help better understand cognitive issues. The trail-making test and the digit symbol substitution test are easy to administer and give meaningful results. They are now available through a free software package, THINC-it (available online at progress.im), that can be used to track progress.

 is crucial; explain that it is common for these problems to continue even after the major episodes have resolved. Similarly, let them know that cognitive recovery is a slow process that requires their active involvement.It also helps for families to hear this message. Families need to allow opportunities for the patient to regain their skills in a judgment-free zone and accept the mistakes that come with these attempts. Too often those opportunities are blocked by criticism, blame, or family members who take over patients’ lives in a well-intentioned effort to prevent failure.

Patients often attribute cognitive problems to mood stabilizers. Although there is a grain of truth to this notion, the greater burden is from the episodes themselves. The strongest 

 of cognitive impairment is the number of past episodes, and episodes with long durations or psychotic features take a particular toll.

 Recovery, then, begins with prevention. Make sure patients understand this point by explaining that “each episode is like a small head injury, and the more episodes you have the worse these cognitive problems will get. Your brain needs time to heal, but it cannot do that if the episodes keep coming back.”

Next, set a reasonable goal in concrete terms. Engage patients by asking them “what would you most like to be able to do if these symptoms improved?” Cognitive remediation therapy improves functioning in bipolar disorder. Remarkably, it does so without bringing about meaningful improvements on objective tests of cognition. Instead, patients develop strategies to compensate for those deficits and implement their strategies in the real world. They learn to use calendars, to-do lists, reminders, and to break complex tasks into simpler steps.

 If rehabilitative therapists are not available, patients can borrow those techniques by setting goals and trouble-shooting their progress with the support of their clinician along the way (

Few treatments have been studied for cognitive symptoms of bipolar disorder, and most of what we know is borrowed from related disorders like schizophrenia and age-related cognitive decline. The general approach is to support the health of the brain and body, with the idea that good cognition flows from well-functioning metabolic, cardiovascular, and circadian systems. The 3 interventions with the 

 for cognition across various populations are aerobic exercise (45 minutes 3 to 5 times a week), diet (Mediterranean, Nordic, or Japanese style), and sleep.

If exercise is too difficult, start with a walk in the woods. Compared to a similar walk in an urban or suburban environment, walking in the woods for 60 to 90 minutes improved cognition in small studies of depression, attention-deficit/hyperactivity disorder (ADHD), and healthy college students.

To address dietary issues, start by introducing a few brain-friendly foods. Simple interventions like adding 1 to 2 daily servings of vegetables, nuts, or fruits (particularly blueberries) have improved cognition and mood in small controlled trials.

 With those in the mix, there is usually less room for the processed, fried, sugary, and fast foods that harm cognition.

Sleep consolidates memory and improves attention, processing speed, and creative problem solving. Unfortunately, sleep does not come easily to individuals with bipolar disorder, and trying to force it is counterproductive. Instead, patients should intervene at the points of the circadian cycle that are within their control (

). In clinical studies, nocturnal darkness helped stabilize mania independent of sleep, and in animal studies it enhanced learning and memory.

 can help but they are less effective than the previous strategies. Puzzles and word games have mild benefits that do not clearly translate into functional change. Some of the best-studied games for mild cognitive impairment are dexterity and so-called “exergames,” such as Wii Bowling. These movement-oriented games further 

 the importance of physical activity for cognitive health.

Bipolar disorder is associated with several medical conditions that can impair cognition, such as obesity, diabetes, cardiovascular disease, and sleep apnea. In the case of diabetes, there is evidence that both metformin and liraglutide improve cognition in mood disorders.

 Herpes simplex virus-1 is associated with worse cognition in bipolar disorder. In a small randomized, double-blind, placebo- controlled trial, valacyclovir improved cognition in this population even in the absence of genital lesions.

Among the mood stabilizers, lamotrigine has the most favorable cognitive profile. It improved cognition in large open-label studies and a post-hoc analysis of controlled trials.

 On the other hand, lamotrigine can cause word-finding problems, particularly in the elderly or when the dose goes above 150 mg/day.

Lithium has cognitive risks and benefits. Although most mood stabilizers have neuroprotective effects, the ones seen with lithium are broader, and there is evidence from 5 controlled trials that lithium 

 dementia in the lower dose range (serum levels of 0.25 to 0.5 mEq/L).

 On the other hand, small impairments in short-term memory and creativity were attributable to lithium in a meta-analysis of clinical data.

Well-designed trials of lithium’s cognitive effects are few, but 1 study looked at cognitive outcomes in 61 patients who were randomized to either lithium or quetiapine after a first-episode mania.

 After a year, those on lithium had greater verbal fluency than those on quetiapine. To test this in practice, ask the patient to name as many unique words as possible that start with the letter “P” in 1 minute.

Although some studies have found that atypical antipsychotics impair cognition, 1 small but well-designed 

 tells a different tale for lurasidone. This study included patients with bipolar disorder who were euthymic but experiencing cognitive problems. The participants were randomized to either open-label lurasidone (average dose 48 mg/day) or treatment as usual. After 6 weeks, the lurasidone-treated patients performed significantly better on a battery of cognitive tests compared to the treatment-as-usual group, with a large effect size of 0.8.

Valproate and carbamazepine are associated with deficits of attention, short-term memory, learning, and motor speed.

 There is no evidence that cognition improves on these 2 anticonvulsants. Furthermore, their cognitive profile was worse than that of lithium or lamotrigine in a naturalistic study.

Overall, mood stabilizers cause small but real cognitive impairments. Lamotrigine, lithium, and lurasidone may improve cognition in some ways and worsen it in others. These responses differ by patient, and the best way to manage them is to fine-tune the dose and change the mood stabilizer when necessary.

Patients with mood disorders often think that their cognitive problems are due to ADHD. About 15% of individuals with bipolar disorder have comorbid ADHD. However, if the symptoms began in adulthood and worsened with the mood episodes, it is unlikely that ADHD is the problem. In practice, this is difficult to tease apart, but some signs may lead the way. ADHD tends to make patients more hyped-up, with restless energy and prominent distractibility. The speech of patients with ADHD is marked by a frenetic, choppy rhythm, and they change topics frequently (even when not hypomanic). In comparison, the cognitive deficits of bipolar disorder have a slower feel and resemble age-related cognitive decline. Words do not come easily, and sentences are short. Forgetfulness, inertia, and indecision predominate.

 have calming effects on patients with ADHD because they treat the hyperactivity. In contrast, patients with bipolar disorder are more likely to feel energized on stimulants. At best, stimulants improve cognitive symptoms associated with bipolar disorder for 6 to 12 months and then tolerance sets in. At worst, they cause mania, mixed states, and psychosis. When genuine ADHD and bipolar disorder coexist, modafinil, armodafinil, clonidine, and guanfacine are safer alternatives. Atomoxetine, which resembles a noradrenergic antidepressant, is not a good alternative.

Besides the previously discussed mood stabilizers, there are few controlled pharmacotherapy trials for the cognitive symptoms of bipolar disorder. Treatments for dementia have failed (donepezil and galantamine), as have pramipexole, n-acetylcysteine, and methylene blue. Although modafinil and armodafinil have not been tested for cognitive symptoms of bipolar disorder, these agents 

 in other populations and have positive effects in bipolar depression.

A positive finding comes from an extract of the ashwagandha plant. This extract improved memory, reaction time, and social 

 in a randomized placebo-controlled trial of patients with bipolar disorder who were euthymic but had cognitive problems (n = 53; effect sizes, 0.26 to 0.62). Unfortunately, this trial has not been replicated, but it is backed by bench studies that found ashwagandha had neuroprotective effects on the hippocampus. The extract is readily available in products with “Sensoril” on the label (target dose, 500 mg/d; starting dose, 250 mg/d for the first week).

Bipolar disorder is defined by its symptoms, but it is the impairment that makes it an illness. Its symptoms, after all, are also part of normal life: elation, sadness, irritability, fatigue, and elevated energy. For many patients, the most painful part of bipolar disorder is the loss of control over their own mind. Most would rather lose control of their right arm than the things that define their selfhood: how they act, what they say, and what they think and feel

Cognitive symptoms extend that loss of control beyond the episodes of mania and depression. Linda Logan, a talented woman who wrote about her struggles with bipolar disorder in a 

 that went viral, explained these deficits were a threat to her identity.

 Even after her mood was stabilized, she “lost my sense of competence ... Word retrieval was difficult and slow ... Clarity of thought, memory, and concentration had all left me. I was slowly fading away.” Logan’s advice to psychiatrists was to “ask about what parts of the self have vanished.”

is the mood disorders section editor for 

the editor in chief of The Carlat Psychiatry Report, and the director of the Mood Treatment Center. He has written several books on mood disorders, most recently 

The author does not accept honoraria from pharmaceutical companies but receives royalties from PESI for

Manic-Depressive Illness: Bipolar Disorders and Recurrent Depression

2. Burdick KE, Millett CE, Bonnín CDM, et al. 

The international consortium investigating neurocognition in bipolar disorder (ICONIC-BD)

3. Torrent C, Bonnin Cdel M, Martínez-Arán A, et al. Efficacy of functional remediation in bipolar disorder: a multicenter randomized controlled study. 

4. Serra MC, Dondero KR, Larkins D, et al. 

Healthy lifestyle and cognition: Interaction between diet and physical activity

5. Berman MG, Kross E, Krpan KM, et al. Interacting with nature improves cognition and affect for individuals with depression. 

6. Travica N, D’Cunha NM, Naumovski N, et al. The effect of blueberry interventions on cognitive performance and mood: a systematic review of randomized controlled trials. 

7. Conner TS, Brookie KL, Carr AC, et al. Let them eat fruit! The effect of fruit and vegetable consumption on psychological well-being in young adults: a randomized controlled trial. 

8. Ren M, Zhang H, Qi J, et al. An almond-based low carbohydrate diet improves depression and glycometabolism in patients with type 2 diabetes through modulating gut microbiota and glp-1: a randomized controlled trial. 

9. Harvey AG, Soehner AM, Kaplan KA, et al. 

Treating insomnia improves mood state, sleep, and functioning in bipolar disorder: a pilot randomized controlled trial

10. Bedrosian TA, Vaughn CA, Galan A, et al. Nocturnal light exposure impairs affective responses in a wavelength-dependent manner. 

11. Heo JY, Kim K, Fava M, et al. Effects of smartphone use with and without blue light at night in healthy adults: a randomized, double-blind, cross-over, placebo-controlled comparison. 

12. Henriksen TE, Skrede S, Fasmer OB, et al. Blue-blocking glasses as additive treatment for mania: a randomized placebo-controlled trial. 

13. Hill NT, Mowszowski L, Naismith SL, et al. 

Computerized cognitive training in older adults with mild cognitive impairment or dementia: a systematic review and meta-analysis

14. Guo M, Mi J, Jiang QM, et al. Metformin may produce antidepressant effects through improvement of cognitive function among depressed patients with diabetes mellitus. 

15. Mansur RB, Ahmed J, Cha DS, et al. Liraglutide promotes improvements in objective measures of cognitive dysfunction in individuals with mood disorders: a pilot, open-label study. 

16. Jancin B. Valacyclovir improves cognition in bipolar patients. 

17. Khan A, Ginsberg LD, Asnis GM, et al. Effect of lamotrigine on cognitive complaints in patients with bipolar I disorder. 

18. Daban C, Martínez-Arán A, Torrent C, et al. Cognitive functioning in bipolar patients receiving lamotrigine: preliminary results. 

19. Kaye NS, Graham J, Roberts J, et al. Effect of open-label lamotrigine as monotherapy and adjunctive therapy on the self-assessed cognitive function scores of patients with bipolar I disorder. 

20. Dell’Osso L, Del Grande C, Gesi C, et al. A new look at an old drug: neuroprotective effects and therapeutic potentials of lithium salts. 

21. Forlenza OV, Radanovic M, Talib LL, Gattaz WF. 

Clinical and biological effects of long-term lithium treatment in older adults with amnestic mild cognitive impairment: randomized clinical trial

22. Wingo AP, Wingo TS, Harvey PD, Baldessarini RJ. Effects of lithium on cognitive performance: a meta-analysis. 

23. Daglas R, Cotton SM, Allott K, et al. A single-blind, randomized controlled trial on the effects of lithium and quetiapine monotherapy on the trajectory of cognitive functioning in first episode mania: a 12-month follow-up study. 

24. Yatham LN, Mackala S, Basivireddy J, et al. 

Lurasidone versus treatment as usual for cognitive impairment in euthymic patients with bipolar I disorder: a randomized, open-label, pilot study

25. Dias VV, Balanzá-Martinez V, Soeiro-de-Souza MG, et al. Pharmacological approaches in bipolar disorders and the impact on cognition: a critical overview. 

26. Gualtieri CT, Johnson LG. Comparative neurocognitive effects of 5 psychotropic anticonvulsants and lithium. 

27. Nunez NA, Singh B, Romo-Nava F, et al. 

Efficacy and tolerability of adjunctive modafinil/armodafinil in bipolar depression: a meta-analysis of randomized controlled trials

28. Chengappa KN, Bowie CR, Schlicht PJ, et al. Randomized placebo-controlled adjunctive study of an extract of withania somnifera for cognitive dysfunction in bipolar disorder. 

The problem with how we treat bipolar disorder

For many patients, the most painful part of bipolar disorder is the loss of control over their own mind. 

Cognition, Bipolar Disorder, and the Self

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.

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 

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

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

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

article by David N. Osser, MD, “Valproic Acid: Overused in Bipolar Disorder?”

. Other authors have taken exception to the National Institute for Health Care and Excellence (NICE) Bipolar Guideline’s similar approach to valproic acid (VPA), namely to avoid this medication in women of child-bearing potential.

 Indeed, we think that to give VPA such a low priority for all patients with bipolar seems like an over-response to VPA’s limitations, as this medicine can be effective and well-tolerated in males, as well as in females not of child-bearing potential (especially in very young or older females). Admittedly, VPA needs to have an extremely low priority in women of child-bearing potential due to the important risks of neurodevelopmental delays and polycystic ovary. The article correctly points out this fact; however, it fails to note mitigating information such as treatments for the latter include hormonal contraceptives.

The article stated that the last 2 VPA studies were negative, and VPA has a small effect size in acute mania.

 However, even though the last 2 controlled trials were negative, perhaps due to methodological limitations, divalproex sodium and divalproex sodium extended release are currently FDA-approved for the treatment of acute mania in monotherapy, in consideration of the efficacy showed by previous results on adults.

 In addition, 1 negative study from the point of view of efficacy was positive from the point of view of safety (rather than efficacy) in children and adolescents.

The article correctly pointed out that VPA was not FDA-approved for bipolar maintenance treatment. However, this may have been due to the “non-enriched” (for acute valproate response) design of the VPA bipolar maintenance study.

 Indeed, VPA can be an effective bipolar maintenance treatment if using an “enriched” (for acute valproate response) design.

 It can be challenging to link logic to FDA-approval status of medications, as several second-generation antipsychotics (SGA) have already been FDA-approved to add to VPA (or lithium) in drug-resistant bipolar maintenance treatment. Additionally, lurasidone was FDA-approved to add to VPA (or lithium) in treatment-resistant acute bipolar depression.

The piece noted that a few small studies (4 studies with 142 participants) have been consistent with VPA efficacy in acute bipolar depression.

 However, in the absence of economic incentive, it may be unlikely that a larger acute bipolar depression VPA study will be undertaken.

VPA may be more effective than lithium in bipolar mania with dysphoria.

Is valproic acid dismissed out of hand? Three doctors discuss its potential as a treatment. 

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Addressing Pain in Patients With Bipolar Disorder

ADHD in Bipolar Patients: Genetics, Diagnosis, and Treatment

Reappraising a Preference for Valproate

Giving Valproic Acid a Higher Priority in Bipolar Patients

Oxcarbazepine: Does It Have a Role in Bipolar Disorder?

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Faith Is Not Enough: Self-Administered Questionnaire Screening for Bipolar Disorder