 is associate professor of psychiatry at Harvard Medical School and Co-Director, US Department of Veterans Affairs National Bipolar Disorder Telehealth Program. 

David N. Osser, MD

(This is the third part of the How To Diagnose Bipolar Disorder series—Ed.)

Have you had difficulty with differential diagnosis when the patient has manic symptoms and psychosis? In 2013, the DSM-5 made the issue clearer with significant changes in the criteria defining the quantity and nature of mood symptoms in these diagnoses. As a result, more patients will be diagnosed with schizophrenia compared with when using DSM-IV in either the TM or later “Text Revised” TR version. I will propose some of the implications for psychopharmacology.

In the schizophrenia D criteria in DSM-5, the patient should have no mood episodes (ie, meeting full criteria for mania or depression) during the active phase of the illness, or, if the patient has episodes, those episodes occur during a minority (ie, up to 50%) of the total duration of the illness (active and residual phases). In other words, a patient with schizophrenia can have a full manic syndrome present for up to 50% of the time, as long as the other schizophrenia criteria are met. Those criteria include, from the A criteria, positive symptoms during the acute phase; the B criteria of illness duration of at least 6 months of the active and residual phases; the C criteria of deterioration in functioning compared to premorbid levels; and the E criteria of no explanation of it from a substance or medical illness.

In the DSM-IV D criteria for schizophrenia, the requirement was that any mood episodes had to be brief in duration compared with the duration of the illness. An example of “brief” was a 5-week period of mania or depression in a patient who was ill for 4 years, which would translate to having a mood syndrome present 2.5% of the time. So, with DSM-IV, individuals with schizophrenia could not experience much time with any mood syndrome to meet the criteria. If mood syndromes were present longer than 2.5% of the time, the diagnosis would be schizoaffective disorder or bipolar with psychosis.

However, the DSM-5 criteria for schizoaffective disorder offer the mirror image of the D criteria for schizophrenia: Here, the individual must meet criteria for a mood syndrome for the majority (ie, 50% or more) of the total time that they have been ill. In DSM-IV, it had to be substantial (ie, more than brief [2.5%]). Diagnosis also requires the other schizoaffective criteria, including 2 weeks of psychosis in the absence of prominent mood symptoms. Here, the term 

, meaning that there cannot be any prominent symptoms—much less the full syndrome—of mania or depression present for those 2 weeks.

There seem to be very few patients who meet these DSM-5 criteria for schizoaffective disorder, which require that they be in a mania (or depression) for the majority of the time and also have psychosis without any significant symptoms of a mood disorder for 2 full weeks. Making it tougher to diagnose schizoaffective disorder was probably intended by the DSM-5 authors. The evidence they considered suggested that the disorder, as defined in DSM-IV, did not exist;

 they wanted to eliminate it. They retained it because of pushback from field trials, with practicing psychiatrists who largely wanted to keep schizoaffective disorder in the manual.

Notably, study results have shown that when the DSM-IV criteria for schizoaffective disorder were in use (1994-2013), clinicians did not seem to use it for diagnoses.

 They overdiagnosed it using unspecified criteria. Also, study results found that patients diagnosed using the criteria very often evolved over time to having a schizophrenia diagnosis, whereas schizophrenia diagnoses under DSM-IV tended to be stable over time.

 Accordingly, with the new, more inclusive DSM-5 criteria for schizophrenia, the diagnosis should continue to be stable.

How about the diagnosis of mania with psychosis? In psychotic mania (in DSM-IV and DSM-5), the psychosis appears only during the time the patient is meeting criteria for mania, not after it as in schizoaffective disorder. Usually, the psychosis develops during the most severe part of the mania and tends to resolve early as the episode improves, and before the rest of the manic symptoms resolve.

Now that you have an accurate diagnosis per DSM-5, what is the psychopharmacology treatment? If the diagnosis turns out to be schizophrenia, there is no demonstrated value to adding non-antipsychotic mood stabilizers (like lithium or valproate) to the antipsychotic for the manic component, according to the evidence reviewed in the Schizophrenia Patient Outcomes Research Team (PORT) guidelines.

 These additions only potentially contribute adverse effects. The usual psychopharmacology algorithm of employing 2 adequate monotherapy trials of antipsychotics followed by consideration of clozapine probably still applies for DSM-5 schizophrenia. If the diagnosis is bipolar with psychosis, you can use those traditional mood stabilizers as well as antipsychotics. Study results show that psychotic mania responds just as well to either class of drugs.

But what if the patient meets the DSM-5 criteria for schizoaffective disorder, bipolar type? We do not know how to treat it, just as we did not know how to treat DSM-IV schizoaffective disorder, bipolar type. There are almost no studies, no algorithms to consult, no FDA-approved options (although some paliperidone products did manage to get the only FDA approval for schizoaffective disorder). There is still serious doubt that the condition even exists as a valid entity, and it is likely that the current criteria capture only some patients who belong in either the schizophrenia spectrum or the bipolar spectrum.

It is suggested that you treat with your best psychopharmacology algorithm for schizophrenia or for bipolar with psychosis, depending on which diagnostic category best represents the patient’s presentation. If the results are unsatisfactory, try switching to your algorithm for the other diagnosis. This may produce better results than improvising with pure guesswork.

is co-director of the VA National Bipolar Disorder Telehealth Program and an associate professor of psychiatry at Harvard Medical School at the VA Boston Healthcare System.

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Boundaries of schizoaffective disorder: revisiting Kraepelin

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Does schizoaffective disorder really exist? a systematic review of the studies that compared schizoaffective disorder with schizophrenia or mood disorders

Current issues on schizoaffective disorder

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Schizoaffective disorder—an ongoing challenge for psychiatric nosology

The stages of mania. a longitudinal analysis of the manic episode

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The Schizophrenia Patient Outcomes Research Team (PORT): updated treatment recommendations 2009

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

Articles

Have you had difficulty with differential diagnosis when patients have manic symptoms and psychosis? One doctor discusses the related DSM-5 criteria changes and some of their implications for psychopharmacology.


Mania With Psychosis vs Schizophrenia vs Schizoaffective Disorder, Bipolar Type

 have focused on lithium’s advantages. The well-known downsides, including renal impairment, have also been discussed. However, a recent consultation reminded me that there is an infrequent, but important, toxic effect of lithium that deserves increased awareness: the Syndrome of Irreversible Lithium-Effectuated Neurotoxicity, or SILENT.

 First named in the 1980s, SILENT was diagnosed in 90 case reports in peer-reviewed publications as of 2005, starting in 1949 when lithium chloride was being used as a substitute for table salt.

The clinical profile of SILENT varies, but persistent cerebellar dysfunction is the most common finding, with extrapyramidal symptoms also typically present. Many of these cases involve insidious progression in patients on normal or low therapeutic levels of 

. The first sign may be decreased alertness or slight apathy, followed by muscular rigidity or fasciculations and mild ataxia. These symptoms increase and become severe, and then impaired consciousness with a stupor-like presentation can develop.

When lithium is stopped, some or all of these symptoms may persist beyond 2 months, with some reports describing continued symptoms for 5 years. Most cases have residual impairments such as ataxia and dysarthria that continue for 1 year. Sometimes there is persisting cognitive dysfunction with memory loss and other symptoms of dementia. In other cases, additional atypical symptoms accompany the core features, including nystagmus, papilledema, and choreoathetoid movements suggestive of tardive dyskinesia.

SILENT’s cause is unknown. Demyelination has been found on biopsy of peripheral nerves and may occur in the cerebellum and elsewhere.

 This may account for the persistence of the neurological sequelae.

Precipitating or predictive factors may include diagnosis of schizoaffective disorder, marked psychosis, abnormal EEG prior to treatment, preexisting neurological illnesses including Alzheimer disease, and fever—especially high fever.

 Readers may recall the famous 1970s cases of neurotoxicity arising from the use of lithium plus haloperidol.

 All patients in those cases had very high fevers and high lithium levels, and they are now thought to have had cases of SILENT. Some other possible contributing factors could be hypertension, heart failure, rapid lowering from high lithium levels, and epilepsy.

To prevent SILENT, it may be helpful to avoid high lithium levels through regular and frequent monitoring (eg, every 4-6 months). If symptoms develop, 

. Treat persisting symptoms with appropriate physical rehabilitation and cognitive training as you would for dementia.

The other side of the coin on lithium neurotoxicity, as discussed in a previous column,

 is the positive neurotrophic effects of lithium that benefit many patients. In a recent pilot study, for example, 12 patients recovering from stroke were prescribed open-label lithium for 60 days (target levels, 0.4-0.6 mEq/L). Gray matter volume as measured by MRI increased numerically (but not significantly; P = .07), and there was a significant correlation between higher lithium dose and gray matter volume increase (P = .004) and improved verbal memory (P = .05).

In conclusion, lithium’s benefits to brain health are substantial, but there are rare cases of serious toxicity that should be detected as early as possible.

is an associate professor of psychiatry at Harvard Medical School and codirector of the US Department of Veterans Affairs’ National Bipolar Disorder Telehealth Program, in Brockton, Massachusetts. The author reports no conflicts of interest concerning the subject matter of this article.

The syndrome of irreversible lithium-effectuated neurotoxicity. 

2. Hanlon LW, Romaine M III, Gilroy FJ, Deitrick JE. 

Lithium chloride as a substitute for sodium chloride in the diet; observations on its toxicity.

Lithium carbonate, haloperidol, and irreversible brain damage.

5. Sun YR, Herrmann N, Scott CJM, et al. 

Lithium carbonate in a poststroke population: exploratory analyses of neuroanatomical and cognitive outcomes.

This infrequent, but important, toxic effect of lithium deserves increased awareness.

Lithium Neurotoxicity: The SILENT Syndrome

The last column discussed how to improve precision in the diagnosis of mania and hypomania and how to identify likely prebipolar depressions that may evolve into a diagnosis of 

 (BD) following the onset of a subsequent manic or hypomanic episode. It is important to identify comorbid disorders that add to the symptoms of BD, so that these symptoms can be targeted appropriately. Some prescribers tend to target symptoms (eg, anxiety, insomnia, and irritability) with medications while leaving the underlying disorder(s) unrecognized and/or untreated.

When there is a comorbidity, one should first delineate the various DSM-5 diagnoses that are present (

). The evaluation may require several meetings to reach the initial diagnostic impression, and it can take 90 minutes to evaluate a complex new patient, including reviewing the previous record and writing the assessment.

 Clinicians who are employed may not be allowed this much time, or if in private practice, they may elect to take less time because of financial considerations and pressures. Experienced clinicians may convince themselves that they can do an adequate assessment in less time and choose the correct medications for the correct diagnoses. However, a competent and comprehensive psychiatric evaluation requires time. Brief evaluations, followed by quick prescribing, are often experienced by patients as rushed and unsatisfying. Confidence in and respect for our profession is undermined by these practices.

 The first clinical encounter is an important moment that sets the stage for the 

After establish the diagnoses, determine (with the patient) those that may be contributing the most to the patient’s distress or dysfunction, and treat those first with what the evidence best supports. For example, active and severe substance use disorders may deserve priority management. 

 and it may be important to persuade the patient to address this before introducing or modifying the medications prescribed for the BD and other disorders.

 (PTSD) is a common comorbidity, especially in veterans. The irritability in PTSD—which can be triggered by events, interactions, or memories of their trauma—is easily mistaken for the irritable mood that is one of the mood types in the A criteria for bipolar mania (along with elevated or expansive mood) in the DSM-5. Valproate is often prescribed for irritable mood thought to be associated with 

, but the PTSD symptoms, including irritability, will likely not respond to it, as was demonstrated in 2 negative controlled studies.

 Determine whether the irritable mood occurs in discrete episodes of mania that last at least several days and are accompanied by the other manic symptoms in the mania criteria (noting that 4 other symptoms are needed if the mood is only irritable). If not, and the irritable mood is invariably occurring when triggered by events that produce reexperiencing and the fight-or-flight adrenalized immediate reactions to those triggers, then it is likely due to PTSD. For these patients, the treatment would likely be more effective with an antiadrenaline agent in the PTSD armamentarium such as prazosin or clonidine.

 (ADHD) is another comorbidity with BD. Most adults with ADHD have emotional dysregulation, which presents as chronic over-reactiveness to stresses.

 This, too, can be confused with the irritable mood of a manic episode. Stimulants have been found effective for this emotional dysregulation as well as for the focus, concentration, and hyperactivity associated with ADHD.

 It is important to make this diagnosis, using the DSM-5 criteria, and consider which symptoms could be attributed to ADHD and which occur mostly or to a greater extent during discreet manic episodes. Stimulants can, in fact, be used to treat ADHD in patients with comorbid BD.

Sleep impairment is seen in comorbid diagnoses. In mania, there is decreased need for sleep, and the treatment of choice would be an antimanic agent rather than a hypnotic. However, often sleep impairment has other causes. There are medical causes, such as sleep apnea, restless leg syndrome (RLS), caffeinism, nocturia from prostate hypertrophy or diabetes, and pain syndromes, etc. Among psychiatric comorbidities, PTSD, which is associated with sleep disturbance, including difficulty initiating sleep and difficulty maintaining it due to nightmares, disturbed awakenings, and night terrors.

A thorough evaluation of insomnia is indicated to identify the leading cause(s), including asking about all examples of PTSD-related sleep disturbance. This is a much better approach than the shortcut of treating the insomnia symptom by proceeding through a list of hypnotics that might include antihistamines, 

, zolpidem, gabapentin, melatonin, trazodone, mirtazapine, quetiapine, valproate, or some combination of these. Depending on the causes, the proper treatment might be continuous positive airway pressure, effective pain management, pramipexole for RLS, reduction of caffeine use, or prazosin for the nightmares and disturbed awakenings of PTSD.

Patients with BD are also prone to anxiety symptoms. It may be reasonable to use antianxiety agents like buspirone, benzodiazepines, or possibly gabapentin. However, there may be another disorder that is the primary cause of the anxiety. PTSD comes up again because the anxiety can be related to events, fears, triggers, and inability to avoid reminders of their trauma. Buspirone and benzodiazepines have not shown efficacy for that kind of anxiety, and antidepressants are probably best avoided in patients with BD. 

, once again, might be the preferred treatment.

Comorbidities in patients with BD are the rule rather than the exception. Good clinical practice requires us to spend the time to complete a comprehensive evaluation to tease out the various comorbidities and then to treat each one appropriately.

is an associate professor of psychiatry at Harvard Medical School and codirector of the US Department of Veterans Affairs’ National Bipolar Disorder Telehealth Program in Brockton, Massachusetts. The author reports no conflicts of interest concerning the subject matter of this article.

Chemotherapy in Psychiatry: Pharmacologic Basis of Treatments for Major Mental Illness.

Psychopharmacology Algorithms: Clinical Guidance From the Psychopharmacology Algorithm Project at the Harvard South Shore Psychiatry Residency Program.

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.

4. Davis LL, Davidson JRT, Ward LC, et al. 

Divalproex in the treatment of posttraumatic stress disorder: a randomized, double-blind, placebo-controlled trial in a veteran population.

5. Hamner MB, Faldowski RA, Robert S, et al. 

A preliminary controlled trial of divalproex in posttraumatic stress disorder.

6. Faraone SV, Banaschewski T, Coghill D, et al. 

The World Federation of ADHD International Consensus Statement: 208 evidence-based conclusions about the disorder.

7. Viktorin A, Rydén E, Thase ME, et al. 

The risk of treatment-emergent mania with methylphenidate in bipolar disorder.

Comorbid PTSD: update on the role of prazosin. 

Sorting Out Comorbidities

Although the DSM-5 diagnostic criteria for a major depressive episode are the same for unipolar and bipolar disorders, these episodes differ in their natural past history (ie, patients with bipolar disorders will have discrete episodes of hypomanias or manias), age of onset, suicide risk, associated comorbidities, and biological correlates. And, most importantly, they differ dramatically in the medications that are effective. Thus, it is critical to diagnose them correctly.

To do so, you must take a good history for 

, because this is where diagnostic error commonly occurs. Start by informing the patient how important it is to have the correct diagnosis for effective treatment and that being wrong about the diagnosis can lead to the wrong treatment—which is at best ineffective and at worst very harmful (eg, antidepressants can cause a malignant transformation in bipolar disorder to a rapid cycling and treatment-resistant condition).

 This warning to the patient hopefully overrides their potential reluctance to disclose manic symptoms because of the stigma of the diagnosis, their enjoyment of the experience, or their belief that it represents their normal mood and energy that they would like to return to and maintain.

 or hypomania. Patients often wake up feeling, for no particular reason, unusually energetic, with thoughts racing about millions of things they want to get done. They want to start new projects, clean and organize the house, add to their possessions, contact neglected friends. They set out to do those projects and then they go-go-go day and night, feeling a lessened need for sleep or maybe skipping sleep completely for a night or so. They almost invariably spend money to fund the ventures or add to hobbies, clothes, or possessions. Often, they already have plenty of what they are buying and they later recognize that the purchases were unnecessary. They discount the importance of other bills, thinking they will figure out how to pay those at some future date, believing the new purchases to be more important.

Explain that during mania their speech is accelerated and increased in quantity and volume. This tends to be noticed by others, who will advise them to “slow down” so they can be understood. Friends and family may see their plans as impractical, unrealistic, or risky, but patients in the grip of mania will ignore this feedback and often lash out and become irritable and defensive. At work, if there are disagreements with the boss, there can be loud arguments, and the person with mania can impulsively quit or get fired, which they later regret.

Their disinhibited speech can also include embarrassing self-disclosures, undiplomatic criticisms of others, or inappropriate sexualized content. Their property can be littered with tools and supplies for projects that were never finished, because when the manic episode ends, they lose all interest in the activity. Parts of their house may be partly demolished in preparation for the project and then stay that way for years, because when the next manic episode begins, they usually start an entirely different project. Make it clear to the patient that the episodes you are talking about last at least a few days and nights, often more.

Factors That May Signal the Need to Change Diagnosis From Unipolar MDD to BD

At this point, stop and see if the patient recognizes these behavioral patterns. If it is unclear, bring up some additional symptoms: social overactivity, hazardous driving patterns, uncharacteristically starting conversations with strangers, and commonly sexual preoccupations and overactivity (this is a cause, although not the only one, of infidelity in established relationships, often resulting in the end of the primary relationship). It is often best to leave inquiries about sexual indiscretions to a later time due to possible embarrassment for them, but by the time you bring it up, you might get a very emphatic response of “absolutely!” about this symptom.

If the patient reports that these events do occur, get details about how long they last, how frequently the behaviors occur, and whether they cause significant impairment in social or work relationships, have legal consequences, or result in financial hardship. This will determine whether the patient meets the criteria for bipolar I or II, and rapid versus nonrapid cycling.

If the patient does not report criteria-meeting manic episodes, it is possible that they have prebipolar depression and could have a hypomanic or manic episode in the future.

 Initial manias have occurred in elderly patients after decades of depressions. A number of factors may predict when a unipolar major depressive disorder diagnosis could change to a bipolar disorder (

 If enough predictors are present, including failure on previous antidepressant trials, consider treating the depression as a 

 and taper off any antidepressants as you do so.

is associate professor of psychiatry at Harvard Medical School and co-director, US Department of Veterans Affairs National Bipolar Disorders Telehealth Program. The author reports no conflicts of interest concerning the subject matter of this article.

Preventing the malignant transformation of bipolar disorder.

2. El-Mallakh RS, Ghaemi SN, Sagduyu K, et al; STEP-BD Investigators. 

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

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

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

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Major depressive episode and bipolar disorders: same DSM-5 diagnostic criteria, but very different disorders. 

Bipolar Depression: How Not to Miss the Diagnosis

Medication decisions during pregnancy are always a challenge, and, since many pregnancies are unplanned, considerations should start well before pregnancy occurs and should be addressed again if the patient becomes pregnant. Patients with bipolar disorder who stop medication during pregnancy can have a relapse rate of 80% for depression, 16% for mania, and 4% for mixed episodes 

 However, many bipolar medications can have harmful effects during pregnancy.

 Relapse Rates for Those Who Stop Medication During Pregnancy

 is the most teratogenic bipolar medication and should be 

avoided in women of childbearing potential 

until all other options have been exhausted.

 Valproate (but not lamotrigine) also is associated with lower intelligence scores in young children who were exposed to it 

 and is associated with an elevated risk of 

autism spectrum disorder and attention-deficit/hyperactivity disorder

 is almost as teratogenic as valproate and is associated with increased spina bifida and vitamin K deficiencies late in pregnancy.

Lithium has fewer malformation risks than valproate and carbamazepine. In a 

, the adjusted risk ratio for any cardiac abnormality was 1.65 compared with unexposed babies.

 The risk rises with higher doses, but it still has been shown to be lower than previously thought. For Ebstein’s anomaly, the risk ratio was 2.66. In absolute numbers, the risk was 0.6% for lithium-exposed infants vs 0.18% for those not exposed. In the most recent meta-analysis, the absolute risk of any cardiac abnormality was 1.2%. The increased risk was limited to 

Note that these observational studies involved comparisons of women with bipolar disorder taking lithium vs those not taking lithium. Rates of cardiac abnormalities are lower in women without bipolar disorder. The study results were often unclear if they excluded women who were on other teratogenic medications or were misusing any substances like alcohol. The authors

 concluded that the risks of lithium exposure during pregnancy are low. The risks associated with mood episode relapse following lithium cessation or lowering the level below the therapeutic range appear, for most women, to exceed the harms of fetal abnormalities or other pregnancy complications associated with continuing lithium.

Thus, lithium is preferred over valproate and carbamazepine. For some patients, lithium should be the first choice. For bipolar depression, the second-generation antipsychotics (eg, lurasidone, quetiapine, cariprazine) are reasonable choices, although the data on safety in pregnancy for the newer drugs are limited. Depot antipsychotics should not be routinely used in pregnancy; infants may show extrapyramidal symptoms for months. Anticholinergic drugs should not be prescribed to pregnant women except for acute, short-term need.

 seem relatively safe with respect to congenital malformations.

 (the second worst option is quetiapine).

 (ECT) during pregnancy warrants more caution than previously thought. It causes fetal heart rate reduction, uterine contraction, and premature labor in up to one-third of cases. In a large survey of case reports, ECT was found to have a child mortality rate of 7%.

 ECT can be used for severe depression, catatonia, medication-resistant illness, extremely high risk for suicide, psychotic agitation, and severe physical decline due to malnutrition, dehydration, or other life-threatening conditions.

Avoid valproate in any woman with the potential to become pregnant. Should the patient become pregnant, it may be too late to discontinue it before harm is done. High-dose folate (4-5 mg daily) has been recommended if valproate or carbamazepine are essential, but the protective effect occurs only if used prior to conception.

Lamotrigine may be considered for bipolar depression.

Prescribe as few drugs as possible—ideally only 1 medication. When pregnancy unexpectedly occurs during treatment, it is usually best to continue the regimen to avoid exposure to additional agents—except if the patient is on valproate or carbamazepine. In such cases, switching to something safer should be considered. Adjust doses as pregnancy progresses. Blood volume expands 30% in the third trimester. Plasma level monitoring is helpful.

is associate professor of psychiatry at Harvard Medical School and co-lead psychiatrist at the US Department of Veterans Affairs, National Telemental Health Center, Bipolar Disorders Telehealth Program, Brockton, Massachusetts. The author reports no conflicts of interest concerning the subject matter of this article.

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Valproic acid monotherapy in pregnancy and major congenital malformations.

Should women of childbearing potential be prescribed valproate? a call to action.

4. Sher J, Frank JW, Doi L, de Caestecker L. 

Failures in reproductive health policy: overcoming the consequences and causes of inaction.

5. Leistikow N, Smith MH, Payne JL, Osborne LM. 

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Neurodevelopment of children exposed in utero to lamotrigine, sodium valproate and carbamazepine.

7. Wiggs KK, Rickert ME, Sujan AC, et al. 

Antiseizure medication use during pregnancy and risk of ASD and ADHD in children.

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11. Patorno E, Huybrechts KF, Bateman BT, et al. 

Lithium use in pregnancy and the risk of cardiac malformations.

12. Fornaro M, Maritan E, Ferranti R, et al. 

Lithium exposure during pregnancy and the postpartum period: a systematic review and meta-analysis of safety and efficacy outcomes.

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Antipsychotic use in pregnancy and the risk for congenital malformations.

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Continuation of atypical antipsychotic medications during early pregnancy and the risk of gestational diabetes.

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The Maudsley Prescribing Guidelines in Psychiatry.

Bipolar disorder and pregnancy: what considerations need to be kept in mind?

Medication Decisions for Women of Childbearing Potential

Have you run out of ideas for your outpatient with resistant bipolar depression? You might consider the results of 

 about the use of bright fluorescent light.

There have been a fair number of previous studies on light therapy for bipolar disorder. Some studies with this modality of treatment, when compared with likely inactive controls, have not shown efficacy for patients whose disease does not have a seasonal component. Other reports suggested a high rate of switching to mania in patients with bipolar disorder when they received early morning light (the usual timing for light treatment targeting nonbipolar depression). Fortunately, 2 studies showed good results for chronotherapy; in these studies, patients were kept up all night and then administered 

 However, midday light might be safer and/or more efficacious based on some theoretical considerations, and more acceptable compared with requiring sleep deprivation.

In a small study of midday light, 46 patients with moderate bipolar depression were randomized to 1 hour of bright white light at noon (7000 lux, which is less than the 10,000 lux usually administered for unipolar depression) or 50 lux dim red placebo light for 6 weeks.

 Patients exhibiting mixed features, as well as those with a history of rapid cycling in the past year, were excluded from the study. Patients with active suicidal ideation, those with any substance use disorder in the past 6 months, and those on melatonin, stimulants, or nonsteroidal anti-inflammatory drugs were also excluded. Thus, at best, the study results apply to a very limited number of patients in comparison with usual practice patients.

The light dose was titrated slowly as a precaution against inducing mania. Participants started with a 15-minute treatment, which increased by 15 minutes weekly until reaching 1 hour at week 4. Most other light treatment protocols start with the full dose, so this was another novel aspect of the approach (in addition to the timing of the light).

The results demonstrated that remission (defined as a score of 8 or less on the primary depression rating scale) was seen by week 6 in 68% of the bright light group vs 22% of the control group. There were no mood polarity switches. Quite notably, there was no difference between the active and placebo groups in the first 3 weeks. Remission in other light therapy studies tend to cluster at week 5, so the time frame for improvement was similar to other protocols despite the ramping up of dose over the first 4 weeks. However, based on the improvement difference seen between active and placebo groups in weeks 4 to 6, it seemed likely that more treatment time could have resulted in further remissions for the treatment group. The findings were 

, which is a term rarely encountered for studies of bipolar depression (except, perhaps, for electroconvulsive therapy).

Effort was made to prevent bias among patients regarding their expectations of the bright light compared with the dim red light. Recorded baseline levels of expectations were equal in the 2 groups and did not change when repeated at study completion. Nevertheless, one cannot be extremely confident that the blind was successful when the treatments looked so different.

Nothing is known about what strategies to employ with midmorning light for maintenance of the therapeutic effects.

The caveat should be offered that new treatments often do well in early studies, but then those results are harder to replicate in subsequent and larger studies. Examples of such include 

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. He also serves as a member of the Editorial Board of 

. Dr Osser has no financial disclosures regarding this article.

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A rare robust finding from a study on bipolar depression. 