Bipolar Disorder

I appreciate Dr. McInnis’s article and his recommendation to monitor the comprehensive metabolic profile, including the calcium level, before and during lithium treatment. There is an association among lithium treatment, hypercalcemia, and hyperparathyroid­ism.^1,2 This can occur by lithium reduc­ing parathyroid hormone suppression or stimulating parathyroid glands.³

Surprisingly, many guidelines do not include a recommendation to monitor the calcium level; however, the International Society for Bipolar Disorders and other experts do rec­ommend obtaining a calcium level before initiating lithium therapy and at least annually thereafter.^1,4 If hyper­calcemia is present, assessing lithium and the parathyroid hormone level is recommended.³

Clinicians can continue lithium and monitor calcium if treatment is beneficial, hypercalcemia is mild, and the patient is asymptomatic.² For a symptomatic patient or one who has significant hypercalcemia, clinicians should consider discon­tinuing lithium and monitoring for a normalizing calcium level.² For patients with significant hypercalce­mia who need lithium therapy, con­sultation with an endocrinologist is advised.³

Jonathan R. Scarff, MD
VA Outpatient Clinic
Spartanburg, South Carolina

Dr. McInnis responds
Generally, calcium is included in the com­prehensive biochemistry panel (Table 1). Typically, magnesium or phosphorus is overlooked, and therefore was specifi­cally included in the table of recommen­dations. There is a complex relationship between lithium and calcium; Dr. Scarff’s points highlight this. It is noteworthy that lithium normalizes the calcium ampli­tude during action potentials in neurons derived from induced pluripotent stem cells from persons with BD¹; this sug­gests that there might be a direct mode of action in BD involving lithium and calcium. This finding further emphasizes the importance of monitoring calcium, and the wise clinician will verify that it is included in the comprehensive bio­chemistry panel.

I appreciate Dr. McInnis’s article and his recommendation to monitor the comprehensive metabolic profile, including the calcium level, before and during lithium treatment. There is an association among lithium treatment, hypercalcemia, and hyperparathyroid­ism.^1,2 This can occur by lithium reduc­ing parathyroid hormone suppression or stimulating parathyroid glands.³

Surprisingly, many guidelines do not include a recommendation to monitor the calcium level; however, the International Society for Bipolar Disorders and other experts do rec­ommend obtaining a calcium level before initiating lithium therapy and at least annually thereafter.^1,4 If hyper­calcemia is present, assessing lithium and the parathyroid hormone level is recommended.³

Clinicians can continue lithium and monitor calcium if treatment is beneficial, hypercalcemia is mild, and the patient is asymptomatic.² For a symptomatic patient or one who has significant hypercalcemia, clinicians should consider discon­tinuing lithium and monitoring for a normalizing calcium level.² For patients with significant hypercalce­mia who need lithium therapy, con­sultation with an endocrinologist is advised.³

Jonathan R. Scarff, MD
VA Outpatient Clinic
Spartanburg, South Carolina

Dr. McInnis responds
Generally, calcium is included in the com­prehensive biochemistry panel (Table 1). Typically, magnesium or phosphorus is overlooked, and therefore was specifi­cally included in the table of recommen­dations. There is a complex relationship between lithium and calcium; Dr. Scarff’s points highlight this. It is noteworthy that lithium normalizes the calcium ampli­tude during action potentials in neurons derived from induced pluripotent stem cells from persons with BD¹; this sug­gests that there might be a direct mode of action in BD involving lithium and calcium. This finding further emphasizes the importance of monitoring calcium, and the wise clinician will verify that it is included in the comprehensive bio­chemistry panel.

I appreciate Dr. McInnis’s article and his recommendation to monitor the comprehensive metabolic profile, including the calcium level, before and during lithium treatment. There is an association among lithium treatment, hypercalcemia, and hyperparathyroid­ism.^1,2 This can occur by lithium reduc­ing parathyroid hormone suppression or stimulating parathyroid glands.³

Surprisingly, many guidelines do not include a recommendation to monitor the calcium level; however, the International Society for Bipolar Disorders and other experts do rec­ommend obtaining a calcium level before initiating lithium therapy and at least annually thereafter.^1,4 If hyper­calcemia is present, assessing lithium and the parathyroid hormone level is recommended.³

Clinicians can continue lithium and monitor calcium if treatment is beneficial, hypercalcemia is mild, and the patient is asymptomatic.² For a symptomatic patient or one who has significant hypercalcemia, clinicians should consider discon­tinuing lithium and monitoring for a normalizing calcium level.² For patients with significant hypercalce­mia who need lithium therapy, con­sultation with an endocrinologist is advised.³

Jonathan R. Scarff, MD
VA Outpatient Clinic
Spartanburg, South Carolina

Dr. McInnis responds
Generally, calcium is included in the com­prehensive biochemistry panel (Table 1). Typically, magnesium or phosphorus is overlooked, and therefore was specifi­cally included in the table of recommen­dations. There is a complex relationship between lithium and calcium; Dr. Scarff’s points highlight this. It is noteworthy that lithium normalizes the calcium ampli­tude during action potentials in neurons derived from induced pluripotent stem cells from persons with BD¹; this sug­gests that there might be a direct mode of action in BD involving lithium and calcium. This finding further emphasizes the importance of monitoring calcium, and the wise clinician will verify that it is included in the comprehensive bio­chemistry panel.

I was astonished that Dr. Melvin G. McInnis’ article on using lithium to treat bipolar disorder (BD) (Current Psychiatry, June 2014, p. 38-44; [http://bit.ly/1sszAUr]) did not address all the potential hazards of the medication. He discussed side effects, but only how to manage them so that patients will adhere to treatment.

I have used lithium for patients with BD, and often it is efficacious, although hazardous in overdose. Lithium toxicity can cause cardiac arrhythmias, and must be monitored closely. In addition, the effects of hydration and exercise on the lithium level, especially during summer, often are ignored.

Two of my patients, an adolescent and an adult, were well-maintained on lithium, adhered to treatment, and had no concurrent medical problems, but developed significant toxicity for no reason that I could determine. The adult had a lithium level of 2.0 mEq/L in the emergency room; the adoles­cent had a lithium level of 1.8 mEq/L. Levels this high are considered poten­tially lethal, and because it happened without warning and without a cause that I could determine, I consider lithium to be one of the riskier mood stabilizers. I still prescribe it, but with great caution.

Dr. McInnis also did not mention the possibility of lithium-induced diabetes insipidus, a condition in which the kid­neys are no longer able to concentrate urine and that is marked by excessive urination, concomitant water intake, and low urine specific gravity. It is uncommon, but I have seen it 3 times in 30 years, in a practice that special­izes in psychotherapy and does not see a high percentage of patients with BD. I consider it a condition that must be kept in mind as we follow our patients in long-term treatment.

Mary Davis, MD
Lancaster, Pennsylvania

Dr. McInnis responds
Dr. Davis raises the issue of lithium toxic­ity and provides examples of 2 patients who developed levels of 2.0 mEq/L and 1.8 mEq/L. These levels clearly are well beyond the toxicity threshold of 1.3 mEq/L, and the patients wisely sought urgent care. These scenarios exemplify the need for regular monitoring of the lithium level—in particular, when there is any change in physical or mental health status. Development of significant tox­icity generally has some lead-time with emerging short-term side effects (out­lined in Table 2 of my article), which underscores the importance of discussing the nature of emerging side effects with your patient.

Dr. Davis is correct in noting that the practitioner must be aware of long-term side effects of lithium. I find it helpful to discuss these effects with the patient in the context of short-term (days or weeks), intermediate (weeks or months), and long-term (months or years) time frames (Table 2). Diabetes insipidus is listed as an intermediate side effect.

I am grateful to Dr. Davis for raising the issue of hydration and summer heat, a con­cern among parents and coaches when student athletes practice strenuously for extended hours.¹ Miller et al² found that the concentration of lithium was between 1.2- and 4.6-fold in forearm sweat compared with serum levels, with the implication that heat-induced sweating may lower lithium levels. Jefferson et al³ studied 4 athletes after a 20-km race and found that all had become dehydrated but had a decrease in the serum lithium level. This is contrary to the widely held belief that excessive sweating predis­poses to lithium toxicity. 

BD is among the more lethal psychi­atric disorders, and lithium is among the few medications shown to mitigate sui­cidal behavior.⁴ As with any medication, lithium is not without risk, and there is a clear need for informed medical manage­ment. Any notable change in health sta­tus or physical activity in a patient taking lithium is worthy of review, with recom­mendations based on knowledge of the patient and medical science.

I was astonished that Dr. Melvin G. McInnis’ article on using lithium to treat bipolar disorder (BD) (Current Psychiatry, June 2014, p. 38-44; [http://bit.ly/1sszAUr]) did not address all the potential hazards of the medication. He discussed side effects, but only how to manage them so that patients will adhere to treatment.

I have used lithium for patients with BD, and often it is efficacious, although hazardous in overdose. Lithium toxicity can cause cardiac arrhythmias, and must be monitored closely. In addition, the effects of hydration and exercise on the lithium level, especially during summer, often are ignored.

Two of my patients, an adolescent and an adult, were well-maintained on lithium, adhered to treatment, and had no concurrent medical problems, but developed significant toxicity for no reason that I could determine. The adult had a lithium level of 2.0 mEq/L in the emergency room; the adoles­cent had a lithium level of 1.8 mEq/L. Levels this high are considered poten­tially lethal, and because it happened without warning and without a cause that I could determine, I consider lithium to be one of the riskier mood stabilizers. I still prescribe it, but with great caution.

Dr. McInnis also did not mention the possibility of lithium-induced diabetes insipidus, a condition in which the kid­neys are no longer able to concentrate urine and that is marked by excessive urination, concomitant water intake, and low urine specific gravity. It is uncommon, but I have seen it 3 times in 30 years, in a practice that special­izes in psychotherapy and does not see a high percentage of patients with BD. I consider it a condition that must be kept in mind as we follow our patients in long-term treatment.

Mary Davis, MD
Lancaster, Pennsylvania

Dr. McInnis responds
Dr. Davis raises the issue of lithium toxic­ity and provides examples of 2 patients who developed levels of 2.0 mEq/L and 1.8 mEq/L. These levels clearly are well beyond the toxicity threshold of 1.3 mEq/L, and the patients wisely sought urgent care. These scenarios exemplify the need for regular monitoring of the lithium level—in particular, when there is any change in physical or mental health status. Development of significant tox­icity generally has some lead-time with emerging short-term side effects (out­lined in Table 2 of my article), which underscores the importance of discussing the nature of emerging side effects with your patient.

Dr. Davis is correct in noting that the practitioner must be aware of long-term side effects of lithium. I find it helpful to discuss these effects with the patient in the context of short-term (days or weeks), intermediate (weeks or months), and long-term (months or years) time frames (Table 2). Diabetes insipidus is listed as an intermediate side effect.

I am grateful to Dr. Davis for raising the issue of hydration and summer heat, a con­cern among parents and coaches when student athletes practice strenuously for extended hours.¹ Miller et al² found that the concentration of lithium was between 1.2- and 4.6-fold in forearm sweat compared with serum levels, with the implication that heat-induced sweating may lower lithium levels. Jefferson et al³ studied 4 athletes after a 20-km race and found that all had become dehydrated but had a decrease in the serum lithium level. This is contrary to the widely held belief that excessive sweating predis­poses to lithium toxicity. 

BD is among the more lethal psychi­atric disorders, and lithium is among the few medications shown to mitigate sui­cidal behavior.⁴ As with any medication, lithium is not without risk, and there is a clear need for informed medical manage­ment. Any notable change in health sta­tus or physical activity in a patient taking lithium is worthy of review, with recom­mendations based on knowledge of the patient and medical science.

I was astonished that Dr. Melvin G. McInnis’ article on using lithium to treat bipolar disorder (BD) (Current Psychiatry, June 2014, p. 38-44; [http://bit.ly/1sszAUr]) did not address all the potential hazards of the medication. He discussed side effects, but only how to manage them so that patients will adhere to treatment.

I have used lithium for patients with BD, and often it is efficacious, although hazardous in overdose. Lithium toxicity can cause cardiac arrhythmias, and must be monitored closely. In addition, the effects of hydration and exercise on the lithium level, especially during summer, often are ignored.

Two of my patients, an adolescent and an adult, were well-maintained on lithium, adhered to treatment, and had no concurrent medical problems, but developed significant toxicity for no reason that I could determine. The adult had a lithium level of 2.0 mEq/L in the emergency room; the adoles­cent had a lithium level of 1.8 mEq/L. Levels this high are considered poten­tially lethal, and because it happened without warning and without a cause that I could determine, I consider lithium to be one of the riskier mood stabilizers. I still prescribe it, but with great caution.

Dr. McInnis also did not mention the possibility of lithium-induced diabetes insipidus, a condition in which the kid­neys are no longer able to concentrate urine and that is marked by excessive urination, concomitant water intake, and low urine specific gravity. It is uncommon, but I have seen it 3 times in 30 years, in a practice that special­izes in psychotherapy and does not see a high percentage of patients with BD. I consider it a condition that must be kept in mind as we follow our patients in long-term treatment.

Mary Davis, MD
Lancaster, Pennsylvania

Dr. McInnis responds
Dr. Davis raises the issue of lithium toxic­ity and provides examples of 2 patients who developed levels of 2.0 mEq/L and 1.8 mEq/L. These levels clearly are well beyond the toxicity threshold of 1.3 mEq/L, and the patients wisely sought urgent care. These scenarios exemplify the need for regular monitoring of the lithium level—in particular, when there is any change in physical or mental health status. Development of significant tox­icity generally has some lead-time with emerging short-term side effects (out­lined in Table 2 of my article), which underscores the importance of discussing the nature of emerging side effects with your patient.

Dr. Davis is correct in noting that the practitioner must be aware of long-term side effects of lithium. I find it helpful to discuss these effects with the patient in the context of short-term (days or weeks), intermediate (weeks or months), and long-term (months or years) time frames (Table 2). Diabetes insipidus is listed as an intermediate side effect.

I am grateful to Dr. Davis for raising the issue of hydration and summer heat, a con­cern among parents and coaches when student athletes practice strenuously for extended hours.¹ Miller et al² found that the concentration of lithium was between 1.2- and 4.6-fold in forearm sweat compared with serum levels, with the implication that heat-induced sweating may lower lithium levels. Jefferson et al³ studied 4 athletes after a 20-km race and found that all had become dehydrated but had a decrease in the serum lithium level. This is contrary to the widely held belief that excessive sweating predis­poses to lithium toxicity. 

BD is among the more lethal psychi­atric disorders, and lithium is among the few medications shown to mitigate sui­cidal behavior.⁴ As with any medication, lithium is not without risk, and there is a clear need for informed medical manage­ment. Any notable change in health sta­tus or physical activity in a patient taking lithium is worthy of review, with recom­mendations based on knowledge of the patient and medical science.

HOLLYWOOD, FLA. – Because there is no clinically significant difference in bipolar spectrum symptom relief offered by either lithium or quetiapine, which mood stabilizer clinicians choose to prescribe should largely depend on what side effects patients can tolerate.

That’s the conclusion of a panel of experts who presented data from the Bipolar CHOICE (Clinical Health Outcomes Initiative in Comparative Effectiveness for Bipolar Disorder) clinical trial at a meeting of the American Society of Clinical Psychopharmacology, formerly known as the New Clinical Drug Evaluation Unit meeting.

By randomly assigning the study’s 482 participating outpatient adults to either lithium or quetiapine, while allowing clinicians to prescribe adjunctive treatment as necessary; and by using a broader-than-usual set of inclusion criteria, the investigators hoped to provide clinicians with "real world" data on how the respective mood stabilizers perform.

"To my knowledge, this is the first randomized comparative effectiveness study of regular, expert care that looks at lithium versus quetiapine strategies of treatment, both with adjunctive personalized treatment when necessary," study coauthor Dr. Andrew A. Nierenberg told the audience in a well-attended session.

"We tortured the data to get a P value to pop out," said Dr. Nierenberg, who is the director of the Bipolar Clinic and Research Program at Massachusetts General Hospital in Boston. "The bottom line was that the treatment strategies, based on either lithium or quetiapine, were very similar. I think the clinical implication is that the choice of treatment really depends on someone’s tolerability. This may resurrect lithium as something [clinicians] should at least consider, because its use has gone down dramatically in the last 20 years or so."

Side effects such as metabolic or sleep disturbances were slightly less frequent in the lithium group, although the difference was not statistically significant; rates of suicidality and discontinuation of medication due to side effects were also similar across the two groups, according to Dr. David E. Kemp of the psychiatry department at Case Western Reserve University, Cleveland, and a study coauthor who also presented data during the session. Changes from baseline in mood stabilization were also virtually the same across the groups.

‘Rules of engagement’

The study enrolled adults aged 18-68 years who were at least mildly ill with either bipolar disorder I (68%) or II, with a Clinical Global Impression (CGI) score of at least 3, although the average CGI score was 4.5 (standard deviation of plus or minus 0.9). Of the 482 enrolled, 364 completed the study.

The so-called rules of engagement for clinicians from the 11 participating centers were that "they do everything they could to get their patients well," with the caveat that the lithium patient group not receive any antipsychotic, and the quetiapine patient group not receive lithium or any other antipsychotic.

"But they could get anything else that they needed," Dr. Nierenberg said.

At the time of enrollment, subjects were, in the estimation of their treating physician, experiencing symptoms that warranted a change in treatment, and that either lithium or quetiapine would be viable therapeutic options. Patients did not need to be lithium- or quetiapine-naive, but they could not have been treated with either drug in the previous 30 days. If they were already taking a second-generation antipsychotic, participants had to be willing to discontinue that medication and to be randomly assigned to either of the study drugs.

This strict adherence to one mood stabilizer, combined with adjunctive personalized treatments such as antidepressants or benzodiazepines, prescribed at the discretion of the treating clinician, ensured that the study tested the strategy of using either lithium or quetiapine as the base of treatment, Dr. Nierenberg said.

‘Similar’ results

Clinicians also were instructed to use the maximum tolerated dose of the respective mood stabilizer. For the 240 patients in the lithium group, the mean maximum tolerated dose was 1,007.5 mg, with the median dose being a "perfectly reasonable 900 mg," Dr. Nierenberg said. Blood lithium levels were taken at weeks 2, 16, and 24 and also were all found to be "reasonable," with most patients getting to at least 0.6 mEq/L by week 24.

For the 242 members of the quetiapine group, the maximum tolerated dose was 344.9 mg, with a median tolerated dose of 300 mg, which Dr. Nierenberg said was "what you would expect."

The overall result was that regardless of which mood stabilizer was prescribed along with adjunctive personalized treatment, the coprimary outcomes of the benefits and harms ratio from treatment effects over time (the CGI efficacy index), and the number of necessary clinical adjustments (changes in medication excluding titrations according to scale), were virtually parallel: For each primary outcome, the P value for the estimated change in baseline was less than .0001 for both lithium plus adjunctive treatment, and quetiapine plus adjunctive treatment.

Further, Dr. Nierenberg reported the "unexpected" result that at 6 months, about a quarter of each group was observed to be doing well without any adjunctive personalized treatments (23.8% of the lithium group; 27.3% of the quetiapine group; P = .14). "We thought that everybody would be on multiple things," Dr. Nierenberg said.

There was also no real difference in the time to discontinuation. "We were actually surprised that at 6 months, about three-quarters of the patients were still on the study drug, which was pretty good considering that this was a very ill population," Dr. Nierenberg said.

Using a CGI bipolar severity scale rating of up to 2, maintained for at least 8 weeks, the investigators found that overall, 20% were considered doing "really well"; it was also about 20% for the lithium plus adjunctive therapy group and the quetiapine and adjunctive therapy group (P = .14 for all three).

Because the Agency for Healthcare Research and Quality–funded study mandated that researchers end their investigation at precisely 36 months, Dr. Nierenberg said the study sites "randomized the 482 patients to 6 months of treatment within 36 months from start to finish," but he added that the investigators would have preferred to conduct a full 2-year study of participants.

"The good news was that most of the patients actually did improve substantially; the bad news is that while maybe a quarter did really well by the end of 6 months, we don’t know whether if we were to extend the study out further, we would see a difference between the two groups, whether they would continue to improve, or whether they would relapse," he said.

Adverse effects, predictors of response

Because study participants were followed for only 6 months, the long-term adverse effects of many years of exposure to either mood stabilizer, such as renal impairment with lithium or type II diabetes with quetiapine, were not considered, Dr. Kemp said. The adverse-effect profile for lithium generally includes a narrow therapeutic index; nausea, vomiting, and diarrhea; renal impairment; and hypothyroidism. Although Dr. Kemp said that the long-term adverse effects of quetiapine are understudied, known short-term side effects include the potential for sedation or somnolence, and weight gain.

Changes in baseline on the Frequency and Intensity of Side Effects Ratings for the quetiapine plus adjunctive personalized treatment arm were slightly more adverse than for the lithium and additional treatment arm. For the lithium plus adjunctive treatment group, the mean frequency of side effects was –1.41 (–1.78, –1.04 SD); the mean intensity of side effects was –1.48 (–1.80, –1.15 SD); and the mean level of impairment was –1.13 (–1.43, –0.82 SD). For the quetiapine and adjunctive treatment group, the mean frequency measure was –1.08 (–1.45, –0.72 SD); the intensity was –1.12 (–1.44, –0.79 SD); and the impairment was –0.77 (–1.07, –0.47 SD). For all scores in both groups, P was less than .001.

The changes from baseline on the Bipolar Index Severity Scale (BISS) overall for the quetiapine plus adjunctive treatment group was –28.56 (–10.91, –26.21 SD; P less than .0001). For the lithium plus adjunctive treatment group, it was –27.61 (–29.99, –25.24 SD; P less than .0001). The overall difference between the two groups was 0.94 (–2.10, 3.99 SD; P = .54).

Scores on the Longitudinal Interval Follow-up Evaluation Range of Impaired Functioning Tool also slightly favored lithium: –3.74 (–4.29, –3.19 SD) vs. –3.6 (–4.15, –3.07 SD) for quetiapine (P less than .0001 for all).

To the investigators’ surprise, among those with comorbid anxiety, the lithium plus adjunctive treatment group had fewer necessary clinical adjustments per month than did the quetiapine plus adjunctive treatment group, according to Dr. Nierenberg: –0.83 vs. 1.11 (P = .02).

"That seemed counterintuitive, and this difference was only with anxiety, not with any other comorbid psychiatric conditions," Dr. Nierenberg said. He hypothesized that it was possible benzodiazepines were used more frequently and easily with lithium than with quetiapine, but said future analyses would give a clearer answer. "We have a detailed database of every other medication used: when it was started, when it was stopped, and the reason why everything was done."

Not having current anxiety disorder was predictive of a better outcome (odds ratio, 1.81; P = .02), as was employment (OR, 1.67; P = .04). Those with bipolar II disorder responded better to treatment than those with bipolar disorder I, having an OR of response to treatment of nearly 1.8 P = .03). "That was a surprise to us, too," Dr. Nierenberg said.

Just over a quarter (27%) of the study population had metabolic syndrome, according to Dr. Kemp, who said this was not found to influence treatment outcomes.

Nearly half of the overall population was obese (48%), and slightly less than half (44%) had adipose. Prospective analysis indicated that patients with either obesity or adiposity tended to show less improvement in their CGI scores in a statistically significant way, regardless of which mood stabilizer they were on.

"Part of that might be due to overlapping pathophysiology between bipolar disorder and obesity," Dr. Kemp said. "Much of that is centered around inflammation in the central nervous system, as well as alterations in adipokines receptor levels and mitochondrial dysfunction."

"A key issue is to take care of obesity," said panel discussant Dr. Mauricio Tohen, chairman of psychiatry at the University of New Mexico in Albuquerque. "Regardless of the treatment, when there is obesity, the outcome will not be as good."

Efficacy vs. ‘generalizability’

Adjunctive personalized treatment was measured to help minimize the lack of assay sensitivity and internal validity typically inherent in comparative effectiveness trials, while also achieving more broadly applicable results.

"The right study depends on the right question," Dr. Tohen said. "If the question is whether a particular treatment has efficacy and is safe, then of course, we need an efficacy study. The problem with efficacy studies is that they limit the generalizability."

Instead, Dr. Tohen, who disclosed he spent more than a decade evaluating efficacy studies for both Eli Lily and AstraZeneca (makers of quetiapine), praised the metric of the adjunctive personalized treatments, and said a study should answer the question, "Of all the patients in my clinic, who will do better on which treatment? With efficacy studies you cannot answer that question because of the exclusion criteria that need to be taken into account."

In addition, Dr. Tohen said the metric likely would increase in importance under the Affordable Care Act, where efficacy is not the only consideration. "For example, if a patient relapses earlier, it might not be reimbursed, so asking what other outcomes we need to measure in [these kinds of] comparative effectiveness studies is very important."

In the CHOICE study, which had no placebo group, participating physicians were asked to track each patient’s dosage changes, missed doses, new medications added, discontinued medications, and the specific reasons for any of these changes. Changes that were made because of lack of effectiveness or intolerance were measured; however, planned dosage titrations according to normal scales were not considered necessary clinical adjustments but simply the regular course of treatment.

This heterogeneity of adjunctive treatment was seen by the investigators as a way to reflect "real world" practice, although they also noted it could be seen as a limitation to the study.

Another way the study was designed to reflect real-world practice was the inclusion of a broader-than-usual group of participants, and asking them for their feedback at the end of the study period.

"Before we put together these data, we held a stakeholder summit," Dr. Nierenberg said. "We invited patients and their advocates to help us interpret the study. They felt strongly that this was a reasonably positive study, because they thought that people really did get better. You could report these data toward the negative or the positive, but we reported toward the positive because that is what the stakeholders asked us to do." Dr. Tohen said that this kind of feedback in a comparative effectiveness study was another way these kinds of studies could help guide practice in the era of the Affordable Care Act.

As for who was actually admitted to the study, "exclusions were minimal," said Dr. Edward S. Friedman of the psychiatry department at the University of Pittsburgh. Those with a history of drug or alcohol dependence in the previous 30 days, a demonstrated intolerance to either study drug, or severe cardiovascular or renal disease were excluded, as were those with unstable thyroid disease, and pregnant or breastfeeding women.

Overall, the group was multiethnic, although nearly three-quarters were white and 20% were black. Roughly a third of the entire study population was employed, a third unemployed, and the rest were students, retirees, or those on disability.

The overall BISS score at enrollment averaged 56.1 (SD plus or minus 18.8). The average BISS depression score was 37.6 (SD plus or minus 14.0), and the average BISS mania score was 18.5 (SD plus or minus 12.1).

There were many comorbid psychiatric conditions, ranging from panic disorder to agoraphobia, although substance use was highest (61.4%). Current anxiety disorder also was prevalent at 58%.

"The CHOICE sample was similar in age and gender to previous efficacy studies," Dr. Friedman said. "It was more representative of the U.S. population than efficacy studies such as STEP-BD or LITMUS."

The 283 women (59% of the study) were more likely to report having spent a greater percentage of time depressed in the previous year, although the percentage of time spent in manic or hypomanic states was equal across both genders.

"This study was composed of sick individuals who had been sick for a considerable period of time," Dr. Friedman said.

For example, in the CHOICE study, 47% had been hospitalized for their bipolar disorder previously, vs. 43% in the LITMUS study. CHOICE participants had an attempted suicide rate of 36%, which fell between the 41% in the LITMUS trial and the 33.3% in an efficacy study conducted by Dr. Joseph R. Calabrese and his colleagues (J. Clin. Psychiatry 1999;60:79-88).

The average age for the first depressive episode for CHOICE participants was 16.4 years; the first manic episode tended to be at 20 years; and the first mood episode tended to be around 15.5 years. These data were similar to those in the LITMUS study, but differed from data in several efficacy studies such as the one by Dr. Calabrese, where the average age was 31.3 years.

"You might anticipate that in these specialty clinics we would have very few medication-naive patients, and yet we did," Dr. Friedman said during a postpanel audience participation session. "Looking for patients with a low threshold, we brought in patients who were very sick. They were also older, with lots of previous episodes. Maybe we missed younger patients who didn’t have as many previous episodes."

"These are the patients you would see in your practice," Dr. Nierenberg said before asking the audience what they think should be studied next in a comparative effectiveness trial. "We could look at the use of different antipsychotics, the combinations we use, with or without lamotrigine," he said.

"Most of the decisions that are made in medicine are made without evidence. Most of the things that are done are done without evidence. You have combinations that were never studied before or never even used before, and it’s across all medicine." Because medicine needs to be learning more, he said the audience needed to participate. "What are the questions that need to be asked?"

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HOLLYWOOD, FLA. – Because there is no clinically significant difference in bipolar spectrum symptom relief offered by either lithium or quetiapine, which mood stabilizer clinicians choose to prescribe should largely depend on what side effects patients can tolerate.

That’s the conclusion of a panel of experts who presented data from the Bipolar CHOICE (Clinical Health Outcomes Initiative in Comparative Effectiveness for Bipolar Disorder) clinical trial at a meeting of the American Society of Clinical Psychopharmacology, formerly known as the New Clinical Drug Evaluation Unit meeting.

By randomly assigning the study’s 482 participating outpatient adults to either lithium or quetiapine, while allowing clinicians to prescribe adjunctive treatment as necessary; and by using a broader-than-usual set of inclusion criteria, the investigators hoped to provide clinicians with "real world" data on how the respective mood stabilizers perform.

"To my knowledge, this is the first randomized comparative effectiveness study of regular, expert care that looks at lithium versus quetiapine strategies of treatment, both with adjunctive personalized treatment when necessary," study coauthor Dr. Andrew A. Nierenberg told the audience in a well-attended session.

"We tortured the data to get a P value to pop out," said Dr. Nierenberg, who is the director of the Bipolar Clinic and Research Program at Massachusetts General Hospital in Boston. "The bottom line was that the treatment strategies, based on either lithium or quetiapine, were very similar. I think the clinical implication is that the choice of treatment really depends on someone’s tolerability. This may resurrect lithium as something [clinicians] should at least consider, because its use has gone down dramatically in the last 20 years or so."

Side effects such as metabolic or sleep disturbances were slightly less frequent in the lithium group, although the difference was not statistically significant; rates of suicidality and discontinuation of medication due to side effects were also similar across the two groups, according to Dr. David E. Kemp of the psychiatry department at Case Western Reserve University, Cleveland, and a study coauthor who also presented data during the session. Changes from baseline in mood stabilization were also virtually the same across the groups.

‘Rules of engagement’

The study enrolled adults aged 18-68 years who were at least mildly ill with either bipolar disorder I (68%) or II, with a Clinical Global Impression (CGI) score of at least 3, although the average CGI score was 4.5 (standard deviation of plus or minus 0.9). Of the 482 enrolled, 364 completed the study.

The so-called rules of engagement for clinicians from the 11 participating centers were that "they do everything they could to get their patients well," with the caveat that the lithium patient group not receive any antipsychotic, and the quetiapine patient group not receive lithium or any other antipsychotic.

"But they could get anything else that they needed," Dr. Nierenberg said.

At the time of enrollment, subjects were, in the estimation of their treating physician, experiencing symptoms that warranted a change in treatment, and that either lithium or quetiapine would be viable therapeutic options. Patients did not need to be lithium- or quetiapine-naive, but they could not have been treated with either drug in the previous 30 days. If they were already taking a second-generation antipsychotic, participants had to be willing to discontinue that medication and to be randomly assigned to either of the study drugs.

This strict adherence to one mood stabilizer, combined with adjunctive personalized treatments such as antidepressants or benzodiazepines, prescribed at the discretion of the treating clinician, ensured that the study tested the strategy of using either lithium or quetiapine as the base of treatment, Dr. Nierenberg said.

‘Similar’ results

Clinicians also were instructed to use the maximum tolerated dose of the respective mood stabilizer. For the 240 patients in the lithium group, the mean maximum tolerated dose was 1,007.5 mg, with the median dose being a "perfectly reasonable 900 mg," Dr. Nierenberg said. Blood lithium levels were taken at weeks 2, 16, and 24 and also were all found to be "reasonable," with most patients getting to at least 0.6 mEq/L by week 24.

For the 242 members of the quetiapine group, the maximum tolerated dose was 344.9 mg, with a median tolerated dose of 300 mg, which Dr. Nierenberg said was "what you would expect."

The overall result was that regardless of which mood stabilizer was prescribed along with adjunctive personalized treatment, the coprimary outcomes of the benefits and harms ratio from treatment effects over time (the CGI efficacy index), and the number of necessary clinical adjustments (changes in medication excluding titrations according to scale), were virtually parallel: For each primary outcome, the P value for the estimated change in baseline was less than .0001 for both lithium plus adjunctive treatment, and quetiapine plus adjunctive treatment.

Further, Dr. Nierenberg reported the "unexpected" result that at 6 months, about a quarter of each group was observed to be doing well without any adjunctive personalized treatments (23.8% of the lithium group; 27.3% of the quetiapine group; P = .14). "We thought that everybody would be on multiple things," Dr. Nierenberg said.

There was also no real difference in the time to discontinuation. "We were actually surprised that at 6 months, about three-quarters of the patients were still on the study drug, which was pretty good considering that this was a very ill population," Dr. Nierenberg said.

Using a CGI bipolar severity scale rating of up to 2, maintained for at least 8 weeks, the investigators found that overall, 20% were considered doing "really well"; it was also about 20% for the lithium plus adjunctive therapy group and the quetiapine and adjunctive therapy group (P = .14 for all three).

Because the Agency for Healthcare Research and Quality–funded study mandated that researchers end their investigation at precisely 36 months, Dr. Nierenberg said the study sites "randomized the 482 patients to 6 months of treatment within 36 months from start to finish," but he added that the investigators would have preferred to conduct a full 2-year study of participants.

"The good news was that most of the patients actually did improve substantially; the bad news is that while maybe a quarter did really well by the end of 6 months, we don’t know whether if we were to extend the study out further, we would see a difference between the two groups, whether they would continue to improve, or whether they would relapse," he said.

Adverse effects, predictors of response

Because study participants were followed for only 6 months, the long-term adverse effects of many years of exposure to either mood stabilizer, such as renal impairment with lithium or type II diabetes with quetiapine, were not considered, Dr. Kemp said. The adverse-effect profile for lithium generally includes a narrow therapeutic index; nausea, vomiting, and diarrhea; renal impairment; and hypothyroidism. Although Dr. Kemp said that the long-term adverse effects of quetiapine are understudied, known short-term side effects include the potential for sedation or somnolence, and weight gain.

Changes in baseline on the Frequency and Intensity of Side Effects Ratings for the quetiapine plus adjunctive personalized treatment arm were slightly more adverse than for the lithium and additional treatment arm. For the lithium plus adjunctive treatment group, the mean frequency of side effects was –1.41 (–1.78, –1.04 SD); the mean intensity of side effects was –1.48 (–1.80, –1.15 SD); and the mean level of impairment was –1.13 (–1.43, –0.82 SD). For the quetiapine and adjunctive treatment group, the mean frequency measure was –1.08 (–1.45, –0.72 SD); the intensity was –1.12 (–1.44, –0.79 SD); and the impairment was –0.77 (–1.07, –0.47 SD). For all scores in both groups, P was less than .001.

The changes from baseline on the Bipolar Index Severity Scale (BISS) overall for the quetiapine plus adjunctive treatment group was –28.56 (–10.91, –26.21 SD; P less than .0001). For the lithium plus adjunctive treatment group, it was –27.61 (–29.99, –25.24 SD; P less than .0001). The overall difference between the two groups was 0.94 (–2.10, 3.99 SD; P = .54).

Scores on the Longitudinal Interval Follow-up Evaluation Range of Impaired Functioning Tool also slightly favored lithium: –3.74 (–4.29, –3.19 SD) vs. –3.6 (–4.15, –3.07 SD) for quetiapine (P less than .0001 for all).

To the investigators’ surprise, among those with comorbid anxiety, the lithium plus adjunctive treatment group had fewer necessary clinical adjustments per month than did the quetiapine plus adjunctive treatment group, according to Dr. Nierenberg: –0.83 vs. 1.11 (P = .02).

"That seemed counterintuitive, and this difference was only with anxiety, not with any other comorbid psychiatric conditions," Dr. Nierenberg said. He hypothesized that it was possible benzodiazepines were used more frequently and easily with lithium than with quetiapine, but said future analyses would give a clearer answer. "We have a detailed database of every other medication used: when it was started, when it was stopped, and the reason why everything was done."

Not having current anxiety disorder was predictive of a better outcome (odds ratio, 1.81; P = .02), as was employment (OR, 1.67; P = .04). Those with bipolar II disorder responded better to treatment than those with bipolar disorder I, having an OR of response to treatment of nearly 1.8 P = .03). "That was a surprise to us, too," Dr. Nierenberg said.

Just over a quarter (27%) of the study population had metabolic syndrome, according to Dr. Kemp, who said this was not found to influence treatment outcomes.

Nearly half of the overall population was obese (48%), and slightly less than half (44%) had adipose. Prospective analysis indicated that patients with either obesity or adiposity tended to show less improvement in their CGI scores in a statistically significant way, regardless of which mood stabilizer they were on.

"Part of that might be due to overlapping pathophysiology between bipolar disorder and obesity," Dr. Kemp said. "Much of that is centered around inflammation in the central nervous system, as well as alterations in adipokines receptor levels and mitochondrial dysfunction."

"A key issue is to take care of obesity," said panel discussant Dr. Mauricio Tohen, chairman of psychiatry at the University of New Mexico in Albuquerque. "Regardless of the treatment, when there is obesity, the outcome will not be as good."

Efficacy vs. ‘generalizability’

Adjunctive personalized treatment was measured to help minimize the lack of assay sensitivity and internal validity typically inherent in comparative effectiveness trials, while also achieving more broadly applicable results.

"The right study depends on the right question," Dr. Tohen said. "If the question is whether a particular treatment has efficacy and is safe, then of course, we need an efficacy study. The problem with efficacy studies is that they limit the generalizability."

Instead, Dr. Tohen, who disclosed he spent more than a decade evaluating efficacy studies for both Eli Lily and AstraZeneca (makers of quetiapine), praised the metric of the adjunctive personalized treatments, and said a study should answer the question, "Of all the patients in my clinic, who will do better on which treatment? With efficacy studies you cannot answer that question because of the exclusion criteria that need to be taken into account."

In addition, Dr. Tohen said the metric likely would increase in importance under the Affordable Care Act, where efficacy is not the only consideration. "For example, if a patient relapses earlier, it might not be reimbursed, so asking what other outcomes we need to measure in [these kinds of] comparative effectiveness studies is very important."

In the CHOICE study, which had no placebo group, participating physicians were asked to track each patient’s dosage changes, missed doses, new medications added, discontinued medications, and the specific reasons for any of these changes. Changes that were made because of lack of effectiveness or intolerance were measured; however, planned dosage titrations according to normal scales were not considered necessary clinical adjustments but simply the regular course of treatment.

This heterogeneity of adjunctive treatment was seen by the investigators as a way to reflect "real world" practice, although they also noted it could be seen as a limitation to the study.

Another way the study was designed to reflect real-world practice was the inclusion of a broader-than-usual group of participants, and asking them for their feedback at the end of the study period.

"Before we put together these data, we held a stakeholder summit," Dr. Nierenberg said. "We invited patients and their advocates to help us interpret the study. They felt strongly that this was a reasonably positive study, because they thought that people really did get better. You could report these data toward the negative or the positive, but we reported toward the positive because that is what the stakeholders asked us to do." Dr. Tohen said that this kind of feedback in a comparative effectiveness study was another way these kinds of studies could help guide practice in the era of the Affordable Care Act.

As for who was actually admitted to the study, "exclusions were minimal," said Dr. Edward S. Friedman of the psychiatry department at the University of Pittsburgh. Those with a history of drug or alcohol dependence in the previous 30 days, a demonstrated intolerance to either study drug, or severe cardiovascular or renal disease were excluded, as were those with unstable thyroid disease, and pregnant or breastfeeding women.

Overall, the group was multiethnic, although nearly three-quarters were white and 20% were black. Roughly a third of the entire study population was employed, a third unemployed, and the rest were students, retirees, or those on disability.

The overall BISS score at enrollment averaged 56.1 (SD plus or minus 18.8). The average BISS depression score was 37.6 (SD plus or minus 14.0), and the average BISS mania score was 18.5 (SD plus or minus 12.1).

There were many comorbid psychiatric conditions, ranging from panic disorder to agoraphobia, although substance use was highest (61.4%). Current anxiety disorder also was prevalent at 58%.

"The CHOICE sample was similar in age and gender to previous efficacy studies," Dr. Friedman said. "It was more representative of the U.S. population than efficacy studies such as STEP-BD or LITMUS."

The 283 women (59% of the study) were more likely to report having spent a greater percentage of time depressed in the previous year, although the percentage of time spent in manic or hypomanic states was equal across both genders.

"This study was composed of sick individuals who had been sick for a considerable period of time," Dr. Friedman said.

For example, in the CHOICE study, 47% had been hospitalized for their bipolar disorder previously, vs. 43% in the LITMUS study. CHOICE participants had an attempted suicide rate of 36%, which fell between the 41% in the LITMUS trial and the 33.3% in an efficacy study conducted by Dr. Joseph R. Calabrese and his colleagues (J. Clin. Psychiatry 1999;60:79-88).

The average age for the first depressive episode for CHOICE participants was 16.4 years; the first manic episode tended to be at 20 years; and the first mood episode tended to be around 15.5 years. These data were similar to those in the LITMUS study, but differed from data in several efficacy studies such as the one by Dr. Calabrese, where the average age was 31.3 years.

"You might anticipate that in these specialty clinics we would have very few medication-naive patients, and yet we did," Dr. Friedman said during a postpanel audience participation session. "Looking for patients with a low threshold, we brought in patients who were very sick. They were also older, with lots of previous episodes. Maybe we missed younger patients who didn’t have as many previous episodes."

"These are the patients you would see in your practice," Dr. Nierenberg said before asking the audience what they think should be studied next in a comparative effectiveness trial. "We could look at the use of different antipsychotics, the combinations we use, with or without lamotrigine," he said.

"Most of the decisions that are made in medicine are made without evidence. Most of the things that are done are done without evidence. You have combinations that were never studied before or never even used before, and it’s across all medicine." Because medicine needs to be learning more, he said the audience needed to participate. "What are the questions that need to be asked?"

[email protected]

On Twitter @whitneymcknight

HOLLYWOOD, FLA. – Because there is no clinically significant difference in bipolar spectrum symptom relief offered by either lithium or quetiapine, which mood stabilizer clinicians choose to prescribe should largely depend on what side effects patients can tolerate.

That’s the conclusion of a panel of experts who presented data from the Bipolar CHOICE (Clinical Health Outcomes Initiative in Comparative Effectiveness for Bipolar Disorder) clinical trial at a meeting of the American Society of Clinical Psychopharmacology, formerly known as the New Clinical Drug Evaluation Unit meeting.

By randomly assigning the study’s 482 participating outpatient adults to either lithium or quetiapine, while allowing clinicians to prescribe adjunctive treatment as necessary; and by using a broader-than-usual set of inclusion criteria, the investigators hoped to provide clinicians with "real world" data on how the respective mood stabilizers perform.

"To my knowledge, this is the first randomized comparative effectiveness study of regular, expert care that looks at lithium versus quetiapine strategies of treatment, both with adjunctive personalized treatment when necessary," study coauthor Dr. Andrew A. Nierenberg told the audience in a well-attended session.

"We tortured the data to get a P value to pop out," said Dr. Nierenberg, who is the director of the Bipolar Clinic and Research Program at Massachusetts General Hospital in Boston. "The bottom line was that the treatment strategies, based on either lithium or quetiapine, were very similar. I think the clinical implication is that the choice of treatment really depends on someone’s tolerability. This may resurrect lithium as something [clinicians] should at least consider, because its use has gone down dramatically in the last 20 years or so."

Side effects such as metabolic or sleep disturbances were slightly less frequent in the lithium group, although the difference was not statistically significant; rates of suicidality and discontinuation of medication due to side effects were also similar across the two groups, according to Dr. David E. Kemp of the psychiatry department at Case Western Reserve University, Cleveland, and a study coauthor who also presented data during the session. Changes from baseline in mood stabilization were also virtually the same across the groups.

‘Rules of engagement’

The study enrolled adults aged 18-68 years who were at least mildly ill with either bipolar disorder I (68%) or II, with a Clinical Global Impression (CGI) score of at least 3, although the average CGI score was 4.5 (standard deviation of plus or minus 0.9). Of the 482 enrolled, 364 completed the study.

The so-called rules of engagement for clinicians from the 11 participating centers were that "they do everything they could to get their patients well," with the caveat that the lithium patient group not receive any antipsychotic, and the quetiapine patient group not receive lithium or any other antipsychotic.

"But they could get anything else that they needed," Dr. Nierenberg said.

At the time of enrollment, subjects were, in the estimation of their treating physician, experiencing symptoms that warranted a change in treatment, and that either lithium or quetiapine would be viable therapeutic options. Patients did not need to be lithium- or quetiapine-naive, but they could not have been treated with either drug in the previous 30 days. If they were already taking a second-generation antipsychotic, participants had to be willing to discontinue that medication and to be randomly assigned to either of the study drugs.

This strict adherence to one mood stabilizer, combined with adjunctive personalized treatments such as antidepressants or benzodiazepines, prescribed at the discretion of the treating clinician, ensured that the study tested the strategy of using either lithium or quetiapine as the base of treatment, Dr. Nierenberg said.

‘Similar’ results

Clinicians also were instructed to use the maximum tolerated dose of the respective mood stabilizer. For the 240 patients in the lithium group, the mean maximum tolerated dose was 1,007.5 mg, with the median dose being a "perfectly reasonable 900 mg," Dr. Nierenberg said. Blood lithium levels were taken at weeks 2, 16, and 24 and also were all found to be "reasonable," with most patients getting to at least 0.6 mEq/L by week 24.

For the 242 members of the quetiapine group, the maximum tolerated dose was 344.9 mg, with a median tolerated dose of 300 mg, which Dr. Nierenberg said was "what you would expect."

The overall result was that regardless of which mood stabilizer was prescribed along with adjunctive personalized treatment, the coprimary outcomes of the benefits and harms ratio from treatment effects over time (the CGI efficacy index), and the number of necessary clinical adjustments (changes in medication excluding titrations according to scale), were virtually parallel: For each primary outcome, the P value for the estimated change in baseline was less than .0001 for both lithium plus adjunctive treatment, and quetiapine plus adjunctive treatment.

Further, Dr. Nierenberg reported the "unexpected" result that at 6 months, about a quarter of each group was observed to be doing well without any adjunctive personalized treatments (23.8% of the lithium group; 27.3% of the quetiapine group; P = .14). "We thought that everybody would be on multiple things," Dr. Nierenberg said.

There was also no real difference in the time to discontinuation. "We were actually surprised that at 6 months, about three-quarters of the patients were still on the study drug, which was pretty good considering that this was a very ill population," Dr. Nierenberg said.

Using a CGI bipolar severity scale rating of up to 2, maintained for at least 8 weeks, the investigators found that overall, 20% were considered doing "really well"; it was also about 20% for the lithium plus adjunctive therapy group and the quetiapine and adjunctive therapy group (P = .14 for all three).

Because the Agency for Healthcare Research and Quality–funded study mandated that researchers end their investigation at precisely 36 months, Dr. Nierenberg said the study sites "randomized the 482 patients to 6 months of treatment within 36 months from start to finish," but he added that the investigators would have preferred to conduct a full 2-year study of participants.

"The good news was that most of the patients actually did improve substantially; the bad news is that while maybe a quarter did really well by the end of 6 months, we don’t know whether if we were to extend the study out further, we would see a difference between the two groups, whether they would continue to improve, or whether they would relapse," he said.

Adverse effects, predictors of response

Because study participants were followed for only 6 months, the long-term adverse effects of many years of exposure to either mood stabilizer, such as renal impairment with lithium or type II diabetes with quetiapine, were not considered, Dr. Kemp said. The adverse-effect profile for lithium generally includes a narrow therapeutic index; nausea, vomiting, and diarrhea; renal impairment; and hypothyroidism. Although Dr. Kemp said that the long-term adverse effects of quetiapine are understudied, known short-term side effects include the potential for sedation or somnolence, and weight gain.

Changes in baseline on the Frequency and Intensity of Side Effects Ratings for the quetiapine plus adjunctive personalized treatment arm were slightly more adverse than for the lithium and additional treatment arm. For the lithium plus adjunctive treatment group, the mean frequency of side effects was –1.41 (–1.78, –1.04 SD); the mean intensity of side effects was –1.48 (–1.80, –1.15 SD); and the mean level of impairment was –1.13 (–1.43, –0.82 SD). For the quetiapine and adjunctive treatment group, the mean frequency measure was –1.08 (–1.45, –0.72 SD); the intensity was –1.12 (–1.44, –0.79 SD); and the impairment was –0.77 (–1.07, –0.47 SD). For all scores in both groups, P was less than .001.

The changes from baseline on the Bipolar Index Severity Scale (BISS) overall for the quetiapine plus adjunctive treatment group was –28.56 (–10.91, –26.21 SD; P less than .0001). For the lithium plus adjunctive treatment group, it was –27.61 (–29.99, –25.24 SD; P less than .0001). The overall difference between the two groups was 0.94 (–2.10, 3.99 SD; P = .54).

Scores on the Longitudinal Interval Follow-up Evaluation Range of Impaired Functioning Tool also slightly favored lithium: –3.74 (–4.29, –3.19 SD) vs. –3.6 (–4.15, –3.07 SD) for quetiapine (P less than .0001 for all).

To the investigators’ surprise, among those with comorbid anxiety, the lithium plus adjunctive treatment group had fewer necessary clinical adjustments per month than did the quetiapine plus adjunctive treatment group, according to Dr. Nierenberg: –0.83 vs. 1.11 (P = .02).

"That seemed counterintuitive, and this difference was only with anxiety, not with any other comorbid psychiatric conditions," Dr. Nierenberg said. He hypothesized that it was possible benzodiazepines were used more frequently and easily with lithium than with quetiapine, but said future analyses would give a clearer answer. "We have a detailed database of every other medication used: when it was started, when it was stopped, and the reason why everything was done."

Not having current anxiety disorder was predictive of a better outcome (odds ratio, 1.81; P = .02), as was employment (OR, 1.67; P = .04). Those with bipolar II disorder responded better to treatment than those with bipolar disorder I, having an OR of response to treatment of nearly 1.8 P = .03). "That was a surprise to us, too," Dr. Nierenberg said.

Just over a quarter (27%) of the study population had metabolic syndrome, according to Dr. Kemp, who said this was not found to influence treatment outcomes.

Nearly half of the overall population was obese (48%), and slightly less than half (44%) had adipose. Prospective analysis indicated that patients with either obesity or adiposity tended to show less improvement in their CGI scores in a statistically significant way, regardless of which mood stabilizer they were on.

"Part of that might be due to overlapping pathophysiology between bipolar disorder and obesity," Dr. Kemp said. "Much of that is centered around inflammation in the central nervous system, as well as alterations in adipokines receptor levels and mitochondrial dysfunction."

"A key issue is to take care of obesity," said panel discussant Dr. Mauricio Tohen, chairman of psychiatry at the University of New Mexico in Albuquerque. "Regardless of the treatment, when there is obesity, the outcome will not be as good."

Efficacy vs. ‘generalizability’

Adjunctive personalized treatment was measured to help minimize the lack of assay sensitivity and internal validity typically inherent in comparative effectiveness trials, while also achieving more broadly applicable results.

"The right study depends on the right question," Dr. Tohen said. "If the question is whether a particular treatment has efficacy and is safe, then of course, we need an efficacy study. The problem with efficacy studies is that they limit the generalizability."

Instead, Dr. Tohen, who disclosed he spent more than a decade evaluating efficacy studies for both Eli Lily and AstraZeneca (makers of quetiapine), praised the metric of the adjunctive personalized treatments, and said a study should answer the question, "Of all the patients in my clinic, who will do better on which treatment? With efficacy studies you cannot answer that question because of the exclusion criteria that need to be taken into account."

In addition, Dr. Tohen said the metric likely would increase in importance under the Affordable Care Act, where efficacy is not the only consideration. "For example, if a patient relapses earlier, it might not be reimbursed, so asking what other outcomes we need to measure in [these kinds of] comparative effectiveness studies is very important."

In the CHOICE study, which had no placebo group, participating physicians were asked to track each patient’s dosage changes, missed doses, new medications added, discontinued medications, and the specific reasons for any of these changes. Changes that were made because of lack of effectiveness or intolerance were measured; however, planned dosage titrations according to normal scales were not considered necessary clinical adjustments but simply the regular course of treatment.

This heterogeneity of adjunctive treatment was seen by the investigators as a way to reflect "real world" practice, although they also noted it could be seen as a limitation to the study.

Another way the study was designed to reflect real-world practice was the inclusion of a broader-than-usual group of participants, and asking them for their feedback at the end of the study period.

"Before we put together these data, we held a stakeholder summit," Dr. Nierenberg said. "We invited patients and their advocates to help us interpret the study. They felt strongly that this was a reasonably positive study, because they thought that people really did get better. You could report these data toward the negative or the positive, but we reported toward the positive because that is what the stakeholders asked us to do." Dr. Tohen said that this kind of feedback in a comparative effectiveness study was another way these kinds of studies could help guide practice in the era of the Affordable Care Act.

As for who was actually admitted to the study, "exclusions were minimal," said Dr. Edward S. Friedman of the psychiatry department at the University of Pittsburgh. Those with a history of drug or alcohol dependence in the previous 30 days, a demonstrated intolerance to either study drug, or severe cardiovascular or renal disease were excluded, as were those with unstable thyroid disease, and pregnant or breastfeeding women.

Overall, the group was multiethnic, although nearly three-quarters were white and 20% were black. Roughly a third of the entire study population was employed, a third unemployed, and the rest were students, retirees, or those on disability.

The overall BISS score at enrollment averaged 56.1 (SD plus or minus 18.8). The average BISS depression score was 37.6 (SD plus or minus 14.0), and the average BISS mania score was 18.5 (SD plus or minus 12.1).

There were many comorbid psychiatric conditions, ranging from panic disorder to agoraphobia, although substance use was highest (61.4%). Current anxiety disorder also was prevalent at 58%.

"The CHOICE sample was similar in age and gender to previous efficacy studies," Dr. Friedman said. "It was more representative of the U.S. population than efficacy studies such as STEP-BD or LITMUS."

The 283 women (59% of the study) were more likely to report having spent a greater percentage of time depressed in the previous year, although the percentage of time spent in manic or hypomanic states was equal across both genders.

"This study was composed of sick individuals who had been sick for a considerable period of time," Dr. Friedman said.

For example, in the CHOICE study, 47% had been hospitalized for their bipolar disorder previously, vs. 43% in the LITMUS study. CHOICE participants had an attempted suicide rate of 36%, which fell between the 41% in the LITMUS trial and the 33.3% in an efficacy study conducted by Dr. Joseph R. Calabrese and his colleagues (J. Clin. Psychiatry 1999;60:79-88).

The average age for the first depressive episode for CHOICE participants was 16.4 years; the first manic episode tended to be at 20 years; and the first mood episode tended to be around 15.5 years. These data were similar to those in the LITMUS study, but differed from data in several efficacy studies such as the one by Dr. Calabrese, where the average age was 31.3 years.

"You might anticipate that in these specialty clinics we would have very few medication-naive patients, and yet we did," Dr. Friedman said during a postpanel audience participation session. "Looking for patients with a low threshold, we brought in patients who were very sick. They were also older, with lots of previous episodes. Maybe we missed younger patients who didn’t have as many previous episodes."

"These are the patients you would see in your practice," Dr. Nierenberg said before asking the audience what they think should be studied next in a comparative effectiveness trial. "We could look at the use of different antipsychotics, the combinations we use, with or without lamotrigine," he said.

"Most of the decisions that are made in medicine are made without evidence. Most of the things that are done are done without evidence. You have combinations that were never studied before or never even used before, and it’s across all medicine." Because medicine needs to be learning more, he said the audience needed to participate. "What are the questions that need to be asked?"

[email protected]

On Twitter @whitneymcknight

As psychiatrists, we are particularly attuned to the value of face-to-face contact with patients. After all, so much is communicated nonverbally.

Fortunately, telepsychiatry has the capacity to give us the information we need to provide effective interventions for patients with mental illness. Even patients with serious mental illness can benefit from these interventions.

Take, for example, a literature review of 390 studies using terms that included "schizophrenia" and/or "telepsychiatry," "telemedicine," or "telepsychology" (Clin. Schizophr. Relat. Psychoses 2014 [doi:10.3371/CSRP.KAFE.021513]). The review, conducted by Dr. John Kasckow of the Veterans Affairs Pittsburgh Health Care System, found that modalities involving the telephone, the Internet, and videoconferencing "appear to be feasible in patients with schizophrenia." Furthermore, they found that those modalities appear to improve patient outcomes, although they acknowledge that more research is needed.

A subset of patients that can benefit from telepsychiatry is those in correctional facilities. Another literature review that looked at the implementation of telepsychiatry in correctional facilities in seven states, including my own state of California, and found that the modality "may improve living conditions and safety inside correctional facilities" (Perm. J. 2013 Summer;17:80-6). This review, conducted by Stacie Anne Deslich of the Marshall University in South Charleston, W.Va., and her colleagues, also found that using telepsychiatry improved access and saved those facilities $12,000 to more than $1 million.

These researchers also called for more study, particularly a case-control examination of the cost of providing psychiatric care through telemedicine vs. face-to-face psychiatric treatment. Using telepsychiatry for this population of patients is particularly important in light of depth and breadth of untreated mental illness in correctional facilities, such as depression, anxiety, bipolar disorders, and schizophrenia. "In addition, costs for providers traveling to distant facilities have been a deterrent to providing adequate care to inmates," Ms. Deslich wrote.

Yet another population of patients that can benefit from telepsychiatry is those with mental illness who come to emergency departments. A program implemented in Elizabeth City, N.C., connected patients in the ED with psychiatric providers who were at remote locations using telemedicine carts that were equipped with wireless technology (ED Manag. 2013;25:121-4). The program’s administrators reported that almost 30% of the patients who had involuntary commitment orders were stabilized to the extent that those orders could be rescinded and they were discharged to outpatient care. Furthermore, the researchers reported, the average length of stay for ED patients who were discharged to inpatient treatment facilities dropped by more than half, from 48 hours to 22.5 hours.

Not so surprisingly, telepsychiatry also is establishing a solid track record among young patients. A study of the perspectives of psychiatrists who provide consultation services to schools found "students were more likely to disclose clinical information via video, compared with face-to-face contact" (Telemed. J.E. Health 2013; 19;794-9). However, the psychiatrists did express concerns about technological difficulties, logistics, and information sharing.

Telepsychiatry also is gaining a foothold in other areas, such as in geriatric and consultation psychiatry. In other settings, telepsychiatry is being introduced, and evidence is still accumulating.

The primary driver of telepsychiatry is the psychiatrist shortage. In 2009, a total of 77% of U.S. counties reported a shortage. Additionally, recent increases in coverage for mental health care create a demand for more psychiatrist time. These factors, coupled with an aging psychiatry workforce, led to a growing imbalance between supply and demand that telepsychiatry can help to alleviate. Telepsychiatry can increase the efficiency of psychiatric care by allowing one psychiatrist to serve patients in multiple settings without burdensome travel. Although telepsychiatry was first used more than 30 years ago, only recently have demographic, economic, and cultural trends led to its rapid expansion.

Opportunities for telepsychiatry implementation exist across the spectrum of psychiatric care. So far, research has shown little or no difference between the outcomes yielded by traditional care and telepsychiatry. Work remains to be done, but clearly telepsychiatry is here to stay.

Dr. Kornbluh is assistant medical director for program improvement and telepsychiatry at the California Department of State Hospitals.

As psychiatrists, we are particularly attuned to the value of face-to-face contact with patients. After all, so much is communicated nonverbally.

Fortunately, telepsychiatry has the capacity to give us the information we need to provide effective interventions for patients with mental illness. Even patients with serious mental illness can benefit from these interventions.

Take, for example, a literature review of 390 studies using terms that included "schizophrenia" and/or "telepsychiatry," "telemedicine," or "telepsychology" (Clin. Schizophr. Relat. Psychoses 2014 [doi:10.3371/CSRP.KAFE.021513]). The review, conducted by Dr. John Kasckow of the Veterans Affairs Pittsburgh Health Care System, found that modalities involving the telephone, the Internet, and videoconferencing "appear to be feasible in patients with schizophrenia." Furthermore, they found that those modalities appear to improve patient outcomes, although they acknowledge that more research is needed.

A subset of patients that can benefit from telepsychiatry is those in correctional facilities. Another literature review that looked at the implementation of telepsychiatry in correctional facilities in seven states, including my own state of California, and found that the modality "may improve living conditions and safety inside correctional facilities" (Perm. J. 2013 Summer;17:80-6). This review, conducted by Stacie Anne Deslich of the Marshall University in South Charleston, W.Va., and her colleagues, also found that using telepsychiatry improved access and saved those facilities $12,000 to more than $1 million.

These researchers also called for more study, particularly a case-control examination of the cost of providing psychiatric care through telemedicine vs. face-to-face psychiatric treatment. Using telepsychiatry for this population of patients is particularly important in light of depth and breadth of untreated mental illness in correctional facilities, such as depression, anxiety, bipolar disorders, and schizophrenia. "In addition, costs for providers traveling to distant facilities have been a deterrent to providing adequate care to inmates," Ms. Deslich wrote.

Yet another population of patients that can benefit from telepsychiatry is those with mental illness who come to emergency departments. A program implemented in Elizabeth City, N.C., connected patients in the ED with psychiatric providers who were at remote locations using telemedicine carts that were equipped with wireless technology (ED Manag. 2013;25:121-4). The program’s administrators reported that almost 30% of the patients who had involuntary commitment orders were stabilized to the extent that those orders could be rescinded and they were discharged to outpatient care. Furthermore, the researchers reported, the average length of stay for ED patients who were discharged to inpatient treatment facilities dropped by more than half, from 48 hours to 22.5 hours.

Not so surprisingly, telepsychiatry also is establishing a solid track record among young patients. A study of the perspectives of psychiatrists who provide consultation services to schools found "students were more likely to disclose clinical information via video, compared with face-to-face contact" (Telemed. J.E. Health 2013; 19;794-9). However, the psychiatrists did express concerns about technological difficulties, logistics, and information sharing.

Telepsychiatry also is gaining a foothold in other areas, such as in geriatric and consultation psychiatry. In other settings, telepsychiatry is being introduced, and evidence is still accumulating.

The primary driver of telepsychiatry is the psychiatrist shortage. In 2009, a total of 77% of U.S. counties reported a shortage. Additionally, recent increases in coverage for mental health care create a demand for more psychiatrist time. These factors, coupled with an aging psychiatry workforce, led to a growing imbalance between supply and demand that telepsychiatry can help to alleviate. Telepsychiatry can increase the efficiency of psychiatric care by allowing one psychiatrist to serve patients in multiple settings without burdensome travel. Although telepsychiatry was first used more than 30 years ago, only recently have demographic, economic, and cultural trends led to its rapid expansion.

Opportunities for telepsychiatry implementation exist across the spectrum of psychiatric care. So far, research has shown little or no difference between the outcomes yielded by traditional care and telepsychiatry. Work remains to be done, but clearly telepsychiatry is here to stay.

Dr. Kornbluh is assistant medical director for program improvement and telepsychiatry at the California Department of State Hospitals.

As psychiatrists, we are particularly attuned to the value of face-to-face contact with patients. After all, so much is communicated nonverbally.

Fortunately, telepsychiatry has the capacity to give us the information we need to provide effective interventions for patients with mental illness. Even patients with serious mental illness can benefit from these interventions.

Take, for example, a literature review of 390 studies using terms that included "schizophrenia" and/or "telepsychiatry," "telemedicine," or "telepsychology" (Clin. Schizophr. Relat. Psychoses 2014 [doi:10.3371/CSRP.KAFE.021513]). The review, conducted by Dr. John Kasckow of the Veterans Affairs Pittsburgh Health Care System, found that modalities involving the telephone, the Internet, and videoconferencing "appear to be feasible in patients with schizophrenia." Furthermore, they found that those modalities appear to improve patient outcomes, although they acknowledge that more research is needed.

A subset of patients that can benefit from telepsychiatry is those in correctional facilities. Another literature review that looked at the implementation of telepsychiatry in correctional facilities in seven states, including my own state of California, and found that the modality "may improve living conditions and safety inside correctional facilities" (Perm. J. 2013 Summer;17:80-6). This review, conducted by Stacie Anne Deslich of the Marshall University in South Charleston, W.Va., and her colleagues, also found that using telepsychiatry improved access and saved those facilities $12,000 to more than $1 million.

These researchers also called for more study, particularly a case-control examination of the cost of providing psychiatric care through telemedicine vs. face-to-face psychiatric treatment. Using telepsychiatry for this population of patients is particularly important in light of depth and breadth of untreated mental illness in correctional facilities, such as depression, anxiety, bipolar disorders, and schizophrenia. "In addition, costs for providers traveling to distant facilities have been a deterrent to providing adequate care to inmates," Ms. Deslich wrote.

Yet another population of patients that can benefit from telepsychiatry is those with mental illness who come to emergency departments. A program implemented in Elizabeth City, N.C., connected patients in the ED with psychiatric providers who were at remote locations using telemedicine carts that were equipped with wireless technology (ED Manag. 2013;25:121-4). The program’s administrators reported that almost 30% of the patients who had involuntary commitment orders were stabilized to the extent that those orders could be rescinded and they were discharged to outpatient care. Furthermore, the researchers reported, the average length of stay for ED patients who were discharged to inpatient treatment facilities dropped by more than half, from 48 hours to 22.5 hours.

Not so surprisingly, telepsychiatry also is establishing a solid track record among young patients. A study of the perspectives of psychiatrists who provide consultation services to schools found "students were more likely to disclose clinical information via video, compared with face-to-face contact" (Telemed. J.E. Health 2013; 19;794-9). However, the psychiatrists did express concerns about technological difficulties, logistics, and information sharing.

Telepsychiatry also is gaining a foothold in other areas, such as in geriatric and consultation psychiatry. In other settings, telepsychiatry is being introduced, and evidence is still accumulating.

The primary driver of telepsychiatry is the psychiatrist shortage. In 2009, a total of 77% of U.S. counties reported a shortage. Additionally, recent increases in coverage for mental health care create a demand for more psychiatrist time. These factors, coupled with an aging psychiatry workforce, led to a growing imbalance between supply and demand that telepsychiatry can help to alleviate. Telepsychiatry can increase the efficiency of psychiatric care by allowing one psychiatrist to serve patients in multiple settings without burdensome travel. Although telepsychiatry was first used more than 30 years ago, only recently have demographic, economic, and cultural trends led to its rapid expansion.

Opportunities for telepsychiatry implementation exist across the spectrum of psychiatric care. So far, research has shown little or no difference between the outcomes yielded by traditional care and telepsychiatry. Work remains to be done, but clearly telepsychiatry is here to stay.

Dr. Kornbluh is assistant medical director for program improvement and telepsychiatry at the California Department of State Hospitals.

I explained to them that schizophrenia is a neurodevelopmental syndrome that comprises hundreds of different disorders of genetic or non-genetic etiology, all of which share a similar psychotic phenotype. Although the various genetic causes of schizophre­nia are difficult to prevent—but may be prevented in the future with epi­genetic techniques—the many non-genetic (environmental) pathways to schizophrenia can be avoided to significantly reduce the incidence of schizophrenia by 40% to 50%, accord­ing to some estimates.

I will share what I told this couple, because even couples without any family history of psychosis may have a child who develops schizophrenia because of a variety of environmental risk factors.

Genetic risk factors
One-half of the 20,000 genes in the 23 chromosomes of the human genome participate in constructing and sculpt­ing the extremely intricate and com­plex human brain. There are many ways that genetic factors can increase the risk of schizophrenia,¹ and only some are transmitted by parents:

Risk genes. More than 30 risk genes have been identified as heritable in schizophrenia. They are spread over many chromosomes and more are likely to be discovered. Most of those risk genes regulate glutamate— not dopamine—pathways, and each increases the risk by 2% to 4%.

Copy number variations (CNVs) are pro­duced via meiosis mishaps, where 1 or 3 alleles of certain genes are formed instead of the usual 2. A high frequency of CNVs have been found in schizophrenia com­pared with the general population—but also are found in autism and bipolar disorders—and are believed to disrupt brain development in various ways.

De novo mutations. Recent studies on large samples of people with schizo­phrenia (50,000 to 100,000) uncovered a much higher rate of mutations (some code for proteins while others are non­sense mutations that code for noth­ing). Obviously, these mutations led to anomalous neurodevelopment.

There are hundreds, maybe thou­sands, of genetic subtypes within the schizophrenia syndrome. Advances in epigenetics, which allow silencing of culprit genes or overexpression of protective genes, one day may enable psychiatric geneticists to prevent schizo­phrenia in fetuses at risk.

Non-genetic risk factors
Just as with the genetic patho-genic heterogeneity, the schizo­phrenia syndrome can be caused by numerous environmental adverse events,² many of which can be avoided, including:

Older paternal age (>45) at time of conception doubles or triples the risk of schizophrenia³ as well as autism and bipolar disorder. Aging sperm are associated with a higher rate of DNA fragmentation and genetic mutations.

Prenatal complications, especially during the second trimester when CNS development takes place. These adverse prenatal events skew fetal brain development to produce psy­chosis in adulthood and can be mini­mized with optimal prenatal care, which sadly is lacking among the poor. These include:
   • Vaginal infections before preg­nancy,⁴ such as herpes simplex virus, can cause fetal brain inflammation and increased risk of schizophrenia.
   • Infections during pregnancy— whether bacterial, viral, or proto­zoan (Toxoplasma gondii)—have been shown to significantly increase the risk of schizophrenia in offspring.⁵ An increase in serum C-reactive protein during pregnancy also is a biomarker of increased risk.
   • Poor diet, especially starva­tion, can double or triple the risk of schizophrenia.
   • Vitamin deficiency, especially folate and vitamin D, are critical for normal brain development.⁶ Vitamin D is vital to mitigate neuroinflammation.
   • Smoking before and during pregnancy.⁴
   • Medical illness during preg­nancy, especially gestational diabetes, increases the risk of schizophrenia in the fetus by 800%.⁷
   • Severe stress during pregnancy, such as the death of the spouse, dou­bles the risk of schizophrenia.²
   • Schizophrenia risk is 400% to 500% higher among those born and raised in an urban area, compared with a rural area.⁸
   • Babies born in northern latitudes, such as in Sweden, Norway, or Canada, have a 10-fold risk of schizophrenia in adulthood compared with babies born near the equator.⁶ This has been attrib­uted to lack of sunshine and the risk of severe vitamin D deficiency in north­ern latitudes.
   • High maternal body mass index during the first trimester⁷ increases the child’s risk of schizophrenia.
   • Low number of prenatal vis­its is associated with higher risk of schizophrenia.
   • Obstetric complications that cause hypoxia and a low Apgar score after birth increase the risk of schizophrenia. This includes long labor, cord around the neck, meco­nium spillage into the amniotic fluid, and mechanical injury with forceps delivery.
   • Infection in the newborn shortly after birth.

Severe physical or sexual abuse before age 5 is associated with increased risk of schizophrenia in adulthood.² This may be because of stress-induced epigenetic mechanisms (silencing or overexpressing certain genes).

Migration has been shown to increase the risk of schizophrenia by 3 to 5 fold. The exact reason is unclear, but it could be a combination of social stress, exposure to new types of germs, less sunshine, and even a different diet.

My advice to the couple? Get a good obstetrician well before conception; get the mother immunized against infections; eat a lot of fish (omega-3 fatty acids); take ade­quate doses of folate and vitamin D, per­haps even choline⁹; avoid smoking before and during pregnancy; adopt a healthy, balanced diet; avoid excessive weight gain and/or gestational diabetes; avoid contact with people with infections; avoid expo­sure to cat feces (toxoplasmosis); sched­ule frequent prenatal visits; and hope for a smooth and uneventful delivery and a newborn with an Apgar score of 9 or 10. All this will greatly reduce the non-genetic risks of schizophrenia, but is unlikely to modify the genetic risks. However, it has been shown that a combination of both genetic and non-genetic risk factors is associated with a more severe form of schizophrenia.¹⁰

Optimal prenatal and postnatal care can be helpful for couples with a family history of schizophrenia (without mov­ing to deliver their baby in a rural village near the equator). However, if their child starts using marijuana during adolescence, all bets are off. The risk of schizophrenia and serious cortical tissue loss increases dramatically when a carrier of risk genes use Cannabis. But that’s another editorial, to be read by clinicians in states where marijuana has been (foolishly, I believe) legalized.

I explained to them that schizophrenia is a neurodevelopmental syndrome that comprises hundreds of different disorders of genetic or non-genetic etiology, all of which share a similar psychotic phenotype. Although the various genetic causes of schizophre­nia are difficult to prevent—but may be prevented in the future with epi­genetic techniques—the many non-genetic (environmental) pathways to schizophrenia can be avoided to significantly reduce the incidence of schizophrenia by 40% to 50%, accord­ing to some estimates.

I will share what I told this couple, because even couples without any family history of psychosis may have a child who develops schizophrenia because of a variety of environmental risk factors.

Genetic risk factors
One-half of the 20,000 genes in the 23 chromosomes of the human genome participate in constructing and sculpt­ing the extremely intricate and com­plex human brain. There are many ways that genetic factors can increase the risk of schizophrenia,¹ and only some are transmitted by parents:

Risk genes. More than 30 risk genes have been identified as heritable in schizophrenia. They are spread over many chromosomes and more are likely to be discovered. Most of those risk genes regulate glutamate— not dopamine—pathways, and each increases the risk by 2% to 4%.

Copy number variations (CNVs) are pro­duced via meiosis mishaps, where 1 or 3 alleles of certain genes are formed instead of the usual 2. A high frequency of CNVs have been found in schizophrenia com­pared with the general population—but also are found in autism and bipolar disorders—and are believed to disrupt brain development in various ways.

De novo mutations. Recent studies on large samples of people with schizo­phrenia (50,000 to 100,000) uncovered a much higher rate of mutations (some code for proteins while others are non­sense mutations that code for noth­ing). Obviously, these mutations led to anomalous neurodevelopment.

There are hundreds, maybe thou­sands, of genetic subtypes within the schizophrenia syndrome. Advances in epigenetics, which allow silencing of culprit genes or overexpression of protective genes, one day may enable psychiatric geneticists to prevent schizo­phrenia in fetuses at risk.

Non-genetic risk factors
Just as with the genetic patho-genic heterogeneity, the schizo­phrenia syndrome can be caused by numerous environmental adverse events,² many of which can be avoided, including:

Older paternal age (>45) at time of conception doubles or triples the risk of schizophrenia³ as well as autism and bipolar disorder. Aging sperm are associated with a higher rate of DNA fragmentation and genetic mutations.

Prenatal complications, especially during the second trimester when CNS development takes place. These adverse prenatal events skew fetal brain development to produce psy­chosis in adulthood and can be mini­mized with optimal prenatal care, which sadly is lacking among the poor. These include:
   • Vaginal infections before preg­nancy,⁴ such as herpes simplex virus, can cause fetal brain inflammation and increased risk of schizophrenia.
   • Infections during pregnancy— whether bacterial, viral, or proto­zoan (Toxoplasma gondii)—have been shown to significantly increase the risk of schizophrenia in offspring.⁵ An increase in serum C-reactive protein during pregnancy also is a biomarker of increased risk.
   • Poor diet, especially starva­tion, can double or triple the risk of schizophrenia.
   • Vitamin deficiency, especially folate and vitamin D, are critical for normal brain development.⁶ Vitamin D is vital to mitigate neuroinflammation.
   • Smoking before and during pregnancy.⁴
   • Medical illness during preg­nancy, especially gestational diabetes, increases the risk of schizophrenia in the fetus by 800%.⁷
   • Severe stress during pregnancy, such as the death of the spouse, dou­bles the risk of schizophrenia.²
   • Schizophrenia risk is 400% to 500% higher among those born and raised in an urban area, compared with a rural area.⁸
   • Babies born in northern latitudes, such as in Sweden, Norway, or Canada, have a 10-fold risk of schizophrenia in adulthood compared with babies born near the equator.⁶ This has been attrib­uted to lack of sunshine and the risk of severe vitamin D deficiency in north­ern latitudes.
   • High maternal body mass index during the first trimester⁷ increases the child’s risk of schizophrenia.
   • Low number of prenatal vis­its is associated with higher risk of schizophrenia.
   • Obstetric complications that cause hypoxia and a low Apgar score after birth increase the risk of schizophrenia. This includes long labor, cord around the neck, meco­nium spillage into the amniotic fluid, and mechanical injury with forceps delivery.
   • Infection in the newborn shortly after birth.

Severe physical or sexual abuse before age 5 is associated with increased risk of schizophrenia in adulthood.² This may be because of stress-induced epigenetic mechanisms (silencing or overexpressing certain genes).

Migration has been shown to increase the risk of schizophrenia by 3 to 5 fold. The exact reason is unclear, but it could be a combination of social stress, exposure to new types of germs, less sunshine, and even a different diet.

My advice to the couple? Get a good obstetrician well before conception; get the mother immunized against infections; eat a lot of fish (omega-3 fatty acids); take ade­quate doses of folate and vitamin D, per­haps even choline⁹; avoid smoking before and during pregnancy; adopt a healthy, balanced diet; avoid excessive weight gain and/or gestational diabetes; avoid contact with people with infections; avoid expo­sure to cat feces (toxoplasmosis); sched­ule frequent prenatal visits; and hope for a smooth and uneventful delivery and a newborn with an Apgar score of 9 or 10. All this will greatly reduce the non-genetic risks of schizophrenia, but is unlikely to modify the genetic risks. However, it has been shown that a combination of both genetic and non-genetic risk factors is associated with a more severe form of schizophrenia.¹⁰

Optimal prenatal and postnatal care can be helpful for couples with a family history of schizophrenia (without mov­ing to deliver their baby in a rural village near the equator). However, if their child starts using marijuana during adolescence, all bets are off. The risk of schizophrenia and serious cortical tissue loss increases dramatically when a carrier of risk genes use Cannabis. But that’s another editorial, to be read by clinicians in states where marijuana has been (foolishly, I believe) legalized.

I explained to them that schizophrenia is a neurodevelopmental syndrome that comprises hundreds of different disorders of genetic or non-genetic etiology, all of which share a similar psychotic phenotype. Although the various genetic causes of schizophre­nia are difficult to prevent—but may be prevented in the future with epi­genetic techniques—the many non-genetic (environmental) pathways to schizophrenia can be avoided to significantly reduce the incidence of schizophrenia by 40% to 50%, accord­ing to some estimates.

I will share what I told this couple, because even couples without any family history of psychosis may have a child who develops schizophrenia because of a variety of environmental risk factors.

Genetic risk factors
One-half of the 20,000 genes in the 23 chromosomes of the human genome participate in constructing and sculpt­ing the extremely intricate and com­plex human brain. There are many ways that genetic factors can increase the risk of schizophrenia,¹ and only some are transmitted by parents:

Risk genes. More than 30 risk genes have been identified as heritable in schizophrenia. They are spread over many chromosomes and more are likely to be discovered. Most of those risk genes regulate glutamate— not dopamine—pathways, and each increases the risk by 2% to 4%.

Copy number variations (CNVs) are pro­duced via meiosis mishaps, where 1 or 3 alleles of certain genes are formed instead of the usual 2. A high frequency of CNVs have been found in schizophrenia com­pared with the general population—but also are found in autism and bipolar disorders—and are believed to disrupt brain development in various ways.

De novo mutations. Recent studies on large samples of people with schizo­phrenia (50,000 to 100,000) uncovered a much higher rate of mutations (some code for proteins while others are non­sense mutations that code for noth­ing). Obviously, these mutations led to anomalous neurodevelopment.

There are hundreds, maybe thou­sands, of genetic subtypes within the schizophrenia syndrome. Advances in epigenetics, which allow silencing of culprit genes or overexpression of protective genes, one day may enable psychiatric geneticists to prevent schizo­phrenia in fetuses at risk.

Non-genetic risk factors
Just as with the genetic patho-genic heterogeneity, the schizo­phrenia syndrome can be caused by numerous environmental adverse events,² many of which can be avoided, including:

Older paternal age (>45) at time of conception doubles or triples the risk of schizophrenia³ as well as autism and bipolar disorder. Aging sperm are associated with a higher rate of DNA fragmentation and genetic mutations.

Prenatal complications, especially during the second trimester when CNS development takes place. These adverse prenatal events skew fetal brain development to produce psy­chosis in adulthood and can be mini­mized with optimal prenatal care, which sadly is lacking among the poor. These include:
   • Vaginal infections before preg­nancy,⁴ such as herpes simplex virus, can cause fetal brain inflammation and increased risk of schizophrenia.
   • Infections during pregnancy— whether bacterial, viral, or proto­zoan (Toxoplasma gondii)—have been shown to significantly increase the risk of schizophrenia in offspring.⁵ An increase in serum C-reactive protein during pregnancy also is a biomarker of increased risk.
   • Poor diet, especially starva­tion, can double or triple the risk of schizophrenia.
   • Vitamin deficiency, especially folate and vitamin D, are critical for normal brain development.⁶ Vitamin D is vital to mitigate neuroinflammation.
   • Smoking before and during pregnancy.⁴
   • Medical illness during preg­nancy, especially gestational diabetes, increases the risk of schizophrenia in the fetus by 800%.⁷
   • Severe stress during pregnancy, such as the death of the spouse, dou­bles the risk of schizophrenia.²
   • Schizophrenia risk is 400% to 500% higher among those born and raised in an urban area, compared with a rural area.⁸
   • Babies born in northern latitudes, such as in Sweden, Norway, or Canada, have a 10-fold risk of schizophrenia in adulthood compared with babies born near the equator.⁶ This has been attrib­uted to lack of sunshine and the risk of severe vitamin D deficiency in north­ern latitudes.
   • High maternal body mass index during the first trimester⁷ increases the child’s risk of schizophrenia.
   • Low number of prenatal vis­its is associated with higher risk of schizophrenia.
   • Obstetric complications that cause hypoxia and a low Apgar score after birth increase the risk of schizophrenia. This includes long labor, cord around the neck, meco­nium spillage into the amniotic fluid, and mechanical injury with forceps delivery.
   • Infection in the newborn shortly after birth.

Severe physical or sexual abuse before age 5 is associated with increased risk of schizophrenia in adulthood.² This may be because of stress-induced epigenetic mechanisms (silencing or overexpressing certain genes).

Migration has been shown to increase the risk of schizophrenia by 3 to 5 fold. The exact reason is unclear, but it could be a combination of social stress, exposure to new types of germs, less sunshine, and even a different diet.

My advice to the couple? Get a good obstetrician well before conception; get the mother immunized against infections; eat a lot of fish (omega-3 fatty acids); take ade­quate doses of folate and vitamin D, per­haps even choline⁹; avoid smoking before and during pregnancy; adopt a healthy, balanced diet; avoid excessive weight gain and/or gestational diabetes; avoid contact with people with infections; avoid expo­sure to cat feces (toxoplasmosis); sched­ule frequent prenatal visits; and hope for a smooth and uneventful delivery and a newborn with an Apgar score of 9 or 10. All this will greatly reduce the non-genetic risks of schizophrenia, but is unlikely to modify the genetic risks. However, it has been shown that a combination of both genetic and non-genetic risk factors is associated with a more severe form of schizophrenia.¹⁰

Optimal prenatal and postnatal care can be helpful for couples with a family history of schizophrenia (without mov­ing to deliver their baby in a rural village near the equator). However, if their child starts using marijuana during adolescence, all bets are off. The risk of schizophrenia and serious cortical tissue loss increases dramatically when a carrier of risk genes use Cannabis. But that’s another editorial, to be read by clinicians in states where marijuana has been (foolishly, I believe) legalized.

HOLLYWOOD, FLA. – Dissociative side effects in patients given a ketamine infusion to treat either major depressive disorder or bipolar disorder predicted a more robust antidepressive response, according to a small secondary analysis.

"Patients who don’t have acute dissociation are more likely not to have antidepressant efficacy in the postinfusion period," Dr. Mark J. Niciu said during an interview discussing his poster presentation at a meeting of the American Society of Clinical Psychopharmacology, formerly known as the New Clinical Drug Evaluation Unit meeting.

"The patients with more disassociation might be the ones to have greater antidepressant efficacy, but they are also the patients we need to keep a closer clinical eye on because they’re having perceptual alterations during the postinfusion period," he said.

Dr. Niciu, a clinical research fellow at the National Institute of Mental Health in Bethesda, Md., reviewed data from 108 treatment-resistant inpatients who met criteria for major depressive disorder or bipolar I or II and were given a subanesthetic ketamine infusion. They examined whether dissociation and psychotic-like experiences, as measured by the Clinician Administered Dissociative States Scale (CADSS), the Brief Psychiatric Rating Scale (BPRS), and the Young Mania Rating Scale (YMRS), and vital sign changes correlated with improvements in the Hamilton Depression Rating Scale (HDRS) at 40 minutes and 230 minutes post infusion, and at 1 and 7 days post infusion.

Pearson correlations indicated that there was a significant association between increased CADSS scores at 40 minutes post infusion and improvement with ketamine in HDRS scores at 230 minutes (r = –0.35, P = .007). Changes in the YMRS or BPRS Positive Symptom score at 40 minutes did not significantly correlate with HDRS improvement at any time point with ketamine. Similarly, none of the vital signs analyzed (changes in systolic or diastolic blood pressure and pulse) significantly correlated to HDRS change.

The question of whether there was an "unblinding" effect was of concern to Dr. Niciu. "The subjects who received ketamine that had greater disassociation might also expect to have greater antidepressive efficacy post infusion," he said. To account for that possibility, he said some researchers are using more active placebos such as midazolam, but he did not think that it was a complete solution because the ideal active placebo would affect glutamate, dopamine, and noradrenaline without having an antidepressant effect.

The overall goal is to discover medications that have keen effects on glutamate receptors such as NMDA (N-methyl-D-aspartate) receptors, as ketamine does, but that do not also have dissociative side effects. "But maybe that’s not possible," Dr. Niciu said. "Maybe we need to have some degree of dissociation as a proxy for the strength of the NMDA receptor blockade because of its antidepressant effects downstream post infusion."

This study was funded by the Intramural Research Program at the National Institute of Mental Health, a NARSAD Independent Investigator Award, and a Brain and Behavior Mood Disorders Research Award. Both of the awards were given to Dr. Carlos A. Zarate.

[email protected]

On Twitter @whitneymcknight

HOLLYWOOD, FLA. – Dissociative side effects in patients given a ketamine infusion to treat either major depressive disorder or bipolar disorder predicted a more robust antidepressive response, according to a small secondary analysis.

"Patients who don’t have acute dissociation are more likely not to have antidepressant efficacy in the postinfusion period," Dr. Mark J. Niciu said during an interview discussing his poster presentation at a meeting of the American Society of Clinical Psychopharmacology, formerly known as the New Clinical Drug Evaluation Unit meeting.

"The patients with more disassociation might be the ones to have greater antidepressant efficacy, but they are also the patients we need to keep a closer clinical eye on because they’re having perceptual alterations during the postinfusion period," he said.

Dr. Niciu, a clinical research fellow at the National Institute of Mental Health in Bethesda, Md., reviewed data from 108 treatment-resistant inpatients who met criteria for major depressive disorder or bipolar I or II and were given a subanesthetic ketamine infusion. They examined whether dissociation and psychotic-like experiences, as measured by the Clinician Administered Dissociative States Scale (CADSS), the Brief Psychiatric Rating Scale (BPRS), and the Young Mania Rating Scale (YMRS), and vital sign changes correlated with improvements in the Hamilton Depression Rating Scale (HDRS) at 40 minutes and 230 minutes post infusion, and at 1 and 7 days post infusion.

Pearson correlations indicated that there was a significant association between increased CADSS scores at 40 minutes post infusion and improvement with ketamine in HDRS scores at 230 minutes (r = –0.35, P = .007). Changes in the YMRS or BPRS Positive Symptom score at 40 minutes did not significantly correlate with HDRS improvement at any time point with ketamine. Similarly, none of the vital signs analyzed (changes in systolic or diastolic blood pressure and pulse) significantly correlated to HDRS change.

The question of whether there was an "unblinding" effect was of concern to Dr. Niciu. "The subjects who received ketamine that had greater disassociation might also expect to have greater antidepressive efficacy post infusion," he said. To account for that possibility, he said some researchers are using more active placebos such as midazolam, but he did not think that it was a complete solution because the ideal active placebo would affect glutamate, dopamine, and noradrenaline without having an antidepressant effect.

The overall goal is to discover medications that have keen effects on glutamate receptors such as NMDA (N-methyl-D-aspartate) receptors, as ketamine does, but that do not also have dissociative side effects. "But maybe that’s not possible," Dr. Niciu said. "Maybe we need to have some degree of dissociation as a proxy for the strength of the NMDA receptor blockade because of its antidepressant effects downstream post infusion."

This study was funded by the Intramural Research Program at the National Institute of Mental Health, a NARSAD Independent Investigator Award, and a Brain and Behavior Mood Disorders Research Award. Both of the awards were given to Dr. Carlos A. Zarate.

[email protected]

On Twitter @whitneymcknight

HOLLYWOOD, FLA. – Dissociative side effects in patients given a ketamine infusion to treat either major depressive disorder or bipolar disorder predicted a more robust antidepressive response, according to a small secondary analysis.

"Patients who don’t have acute dissociation are more likely not to have antidepressant efficacy in the postinfusion period," Dr. Mark J. Niciu said during an interview discussing his poster presentation at a meeting of the American Society of Clinical Psychopharmacology, formerly known as the New Clinical Drug Evaluation Unit meeting.

"The patients with more disassociation might be the ones to have greater antidepressant efficacy, but they are also the patients we need to keep a closer clinical eye on because they’re having perceptual alterations during the postinfusion period," he said.

Dr. Niciu, a clinical research fellow at the National Institute of Mental Health in Bethesda, Md., reviewed data from 108 treatment-resistant inpatients who met criteria for major depressive disorder or bipolar I or II and were given a subanesthetic ketamine infusion. They examined whether dissociation and psychotic-like experiences, as measured by the Clinician Administered Dissociative States Scale (CADSS), the Brief Psychiatric Rating Scale (BPRS), and the Young Mania Rating Scale (YMRS), and vital sign changes correlated with improvements in the Hamilton Depression Rating Scale (HDRS) at 40 minutes and 230 minutes post infusion, and at 1 and 7 days post infusion.

Pearson correlations indicated that there was a significant association between increased CADSS scores at 40 minutes post infusion and improvement with ketamine in HDRS scores at 230 minutes (r = –0.35, P = .007). Changes in the YMRS or BPRS Positive Symptom score at 40 minutes did not significantly correlate with HDRS improvement at any time point with ketamine. Similarly, none of the vital signs analyzed (changes in systolic or diastolic blood pressure and pulse) significantly correlated to HDRS change.

The question of whether there was an "unblinding" effect was of concern to Dr. Niciu. "The subjects who received ketamine that had greater disassociation might also expect to have greater antidepressive efficacy post infusion," he said. To account for that possibility, he said some researchers are using more active placebos such as midazolam, but he did not think that it was a complete solution because the ideal active placebo would affect glutamate, dopamine, and noradrenaline without having an antidepressant effect.

The overall goal is to discover medications that have keen effects on glutamate receptors such as NMDA (N-methyl-D-aspartate) receptors, as ketamine does, but that do not also have dissociative side effects. "But maybe that’s not possible," Dr. Niciu said. "Maybe we need to have some degree of dissociation as a proxy for the strength of the NMDA receptor blockade because of its antidepressant effects downstream post infusion."

This study was funded by the Intramural Research Program at the National Institute of Mental Health, a NARSAD Independent Investigator Award, and a Brain and Behavior Mood Disorders Research Award. Both of the awards were given to Dr. Carlos A. Zarate.

[email protected]

On Twitter @whitneymcknight

HOLLYWOOD, FLA. – Lurasidone as monotherapy in the dosage range of either 20-60 mg/day* or 80-120 mg/day significantly improved functioning and quality-of-life in patients with bipolar depression, a post hoc analysis has shown.

In a previously published study of 318 patients randomized to either lurasidone dosage groups or placebo, the drug’s association at both dose ranges with reduced Montgomery-sberg Depression Scale total scores and Clinical Global Impressions scale for bipolar depression severity scores from baseline to week 6 was significant. The study also noted that both lurasidone groups had significant improvements in patient-reported measures of quality of life and functional impairment, compared with the placebo group (P less than .001 for each) (Am. J. Psychiatry 2014;171:160-8).

The findings led Dr. Terence A. Ketter, professor of psychiatry and chief of the bipolar disorders clinic at Stanford (Calif.) University, to wonder how the improvements in functionality and quality of life had happened in such relatively short order.

"It kind of makes sense that it’s related to the mood improvement," Dr. Ketter said in an interview during a poster session at a meeting of the American Society of Clinical Psychopharmacology, formerly known as the New Clinical Drug Evaluation Unit meeting.

To investigate further, Dr. Ketter and his colleagues performed a mediation regression analysis using data from phase III of the original trial. The results were that reduced depressive symptoms from baseline to week 6 mediated the effect of lurasidone on Sheehan Disability Scale functional recovery and Quality of Life Enjoyment and Satisfaction Questionnaire scores at week 6 (P less than .05 for each).

"This suggests that, at least in the first 6 weeks, most of the improvement [in functionality and quality of life] is related to the improvement in depressive symptoms," Dr. Ketter said. "Functional recovery is something that takes months, and it may be that beyond this by a month or two, you’re looking at a degree of mood improvement by duration interaction to get functional improvement." He added that there likely would be a "huge improvement" in cognition, simply because of the removal of depressive symptoms.

"Is it enough to be able to go out and get a job? Well, maybe not. Maybe you need things to integrate for months before you can go out and work." But, he added, over time, the less interference with one’s cognitive ability, the greater likelihood that person is employable.

In the original study in bipolar I patients, "the company wanted to know which was the right dose," Dr. Ketter said. "As it turned out, both worked. The higher one was a little bit harder to tolerate, but not horribly so."

As a result, Dr. Ketter said the drug has a "pretty flexible label." In his own practice, he said he starts patients on monotherapy with lurasidone 20 mg/day at dinner time, titrating upward in 20-mg increments each week until his patients reach the dosage that works best for them. "The average dose seems to be about 60 mg/day," he said.

Lurasidone, a second-generation antipsychotic, originally was approved by the Food and Drug Administration in 2010 to treat schizophrenia in adults; the indication was expanded in 2013 to include bipolar I, either as monotherapy or as an adjunct to lithium or valproate.

Because of its relatively low impact on metabolic function and its low sedative effect, compared with other second-generation antipsychotics, Dr. Ketter said he favors using lurasidone in his patients. "It’s like an easier to use quetiapine," he noted.

This study was supported by Sunovion Pharmaceuticals. Dr. Ketter disclosed that he has received funding from Sunovion, as well as from AstraZeneca Pharmaceuticals, Cephalon, Eli Lilly, and others.

[email protected]

On Twitter @whitneymcknight

*Correction, 7/2/2014: An earlier version of this story misstated the lurasidone dosage range.

HOLLYWOOD, FLA. – Lurasidone as monotherapy in the dosage range of either 20-60 mg/day* or 80-120 mg/day significantly improved functioning and quality-of-life in patients with bipolar depression, a post hoc analysis has shown.

In a previously published study of 318 patients randomized to either lurasidone dosage groups or placebo, the drug’s association at both dose ranges with reduced Montgomery-sberg Depression Scale total scores and Clinical Global Impressions scale for bipolar depression severity scores from baseline to week 6 was significant. The study also noted that both lurasidone groups had significant improvements in patient-reported measures of quality of life and functional impairment, compared with the placebo group (P less than .001 for each) (Am. J. Psychiatry 2014;171:160-8).

The findings led Dr. Terence A. Ketter, professor of psychiatry and chief of the bipolar disorders clinic at Stanford (Calif.) University, to wonder how the improvements in functionality and quality of life had happened in such relatively short order.

"It kind of makes sense that it’s related to the mood improvement," Dr. Ketter said in an interview during a poster session at a meeting of the American Society of Clinical Psychopharmacology, formerly known as the New Clinical Drug Evaluation Unit meeting.

To investigate further, Dr. Ketter and his colleagues performed a mediation regression analysis using data from phase III of the original trial. The results were that reduced depressive symptoms from baseline to week 6 mediated the effect of lurasidone on Sheehan Disability Scale functional recovery and Quality of Life Enjoyment and Satisfaction Questionnaire scores at week 6 (P less than .05 for each).

"This suggests that, at least in the first 6 weeks, most of the improvement [in functionality and quality of life] is related to the improvement in depressive symptoms," Dr. Ketter said. "Functional recovery is something that takes months, and it may be that beyond this by a month or two, you’re looking at a degree of mood improvement by duration interaction to get functional improvement." He added that there likely would be a "huge improvement" in cognition, simply because of the removal of depressive symptoms.

"Is it enough to be able to go out and get a job? Well, maybe not. Maybe you need things to integrate for months before you can go out and work." But, he added, over time, the less interference with one’s cognitive ability, the greater likelihood that person is employable.

In the original study in bipolar I patients, "the company wanted to know which was the right dose," Dr. Ketter said. "As it turned out, both worked. The higher one was a little bit harder to tolerate, but not horribly so."

As a result, Dr. Ketter said the drug has a "pretty flexible label." In his own practice, he said he starts patients on monotherapy with lurasidone 20 mg/day at dinner time, titrating upward in 20-mg increments each week until his patients reach the dosage that works best for them. "The average dose seems to be about 60 mg/day," he said.

Lurasidone, a second-generation antipsychotic, originally was approved by the Food and Drug Administration in 2010 to treat schizophrenia in adults; the indication was expanded in 2013 to include bipolar I, either as monotherapy or as an adjunct to lithium or valproate.

Because of its relatively low impact on metabolic function and its low sedative effect, compared with other second-generation antipsychotics, Dr. Ketter said he favors using lurasidone in his patients. "It’s like an easier to use quetiapine," he noted.

This study was supported by Sunovion Pharmaceuticals. Dr. Ketter disclosed that he has received funding from Sunovion, as well as from AstraZeneca Pharmaceuticals, Cephalon, Eli Lilly, and others.

[email protected]

On Twitter @whitneymcknight

*Correction, 7/2/2014: An earlier version of this story misstated the lurasidone dosage range.

HOLLYWOOD, FLA. – Lurasidone as monotherapy in the dosage range of either 20-60 mg/day* or 80-120 mg/day significantly improved functioning and quality-of-life in patients with bipolar depression, a post hoc analysis has shown.

In a previously published study of 318 patients randomized to either lurasidone dosage groups or placebo, the drug’s association at both dose ranges with reduced Montgomery-sberg Depression Scale total scores and Clinical Global Impressions scale for bipolar depression severity scores from baseline to week 6 was significant. The study also noted that both lurasidone groups had significant improvements in patient-reported measures of quality of life and functional impairment, compared with the placebo group (P less than .001 for each) (Am. J. Psychiatry 2014;171:160-8).

The findings led Dr. Terence A. Ketter, professor of psychiatry and chief of the bipolar disorders clinic at Stanford (Calif.) University, to wonder how the improvements in functionality and quality of life had happened in such relatively short order.

"It kind of makes sense that it’s related to the mood improvement," Dr. Ketter said in an interview during a poster session at a meeting of the American Society of Clinical Psychopharmacology, formerly known as the New Clinical Drug Evaluation Unit meeting.

To investigate further, Dr. Ketter and his colleagues performed a mediation regression analysis using data from phase III of the original trial. The results were that reduced depressive symptoms from baseline to week 6 mediated the effect of lurasidone on Sheehan Disability Scale functional recovery and Quality of Life Enjoyment and Satisfaction Questionnaire scores at week 6 (P less than .05 for each).

"This suggests that, at least in the first 6 weeks, most of the improvement [in functionality and quality of life] is related to the improvement in depressive symptoms," Dr. Ketter said. "Functional recovery is something that takes months, and it may be that beyond this by a month or two, you’re looking at a degree of mood improvement by duration interaction to get functional improvement." He added that there likely would be a "huge improvement" in cognition, simply because of the removal of depressive symptoms.

"Is it enough to be able to go out and get a job? Well, maybe not. Maybe you need things to integrate for months before you can go out and work." But, he added, over time, the less interference with one’s cognitive ability, the greater likelihood that person is employable.

In the original study in bipolar I patients, "the company wanted to know which was the right dose," Dr. Ketter said. "As it turned out, both worked. The higher one was a little bit harder to tolerate, but not horribly so."

As a result, Dr. Ketter said the drug has a "pretty flexible label." In his own practice, he said he starts patients on monotherapy with lurasidone 20 mg/day at dinner time, titrating upward in 20-mg increments each week until his patients reach the dosage that works best for them. "The average dose seems to be about 60 mg/day," he said.

Lurasidone, a second-generation antipsychotic, originally was approved by the Food and Drug Administration in 2010 to treat schizophrenia in adults; the indication was expanded in 2013 to include bipolar I, either as monotherapy or as an adjunct to lithium or valproate.

Because of its relatively low impact on metabolic function and its low sedative effect, compared with other second-generation antipsychotics, Dr. Ketter said he favors using lurasidone in his patients. "It’s like an easier to use quetiapine," he noted.

This study was supported by Sunovion Pharmaceuticals. Dr. Ketter disclosed that he has received funding from Sunovion, as well as from AstraZeneca Pharmaceuticals, Cephalon, Eli Lilly, and others.

[email protected]

On Twitter @whitneymcknight

*Correction, 7/2/2014: An earlier version of this story misstated the lurasidone dosage range.