The final assignment for this class will be a 10-page critical review of the drug treatment for a psychiatric disorder (broadly defined to include psychological and neurological disorders as well). Th

o cTo Be r 2010 T h e Br o w n Un i v e r s iTy Ps y c h o Ph a r m a c o l o g y UPd a Te 7 continued on next page and p=0.0005, respectively), with no sig- nificant between-group differences.

There were no serious adverse events reported with fluoxetine, which appeared to be well tolerated, with only 2 participants maintained on less than 40 mg/day.

Authors’ conclusions According to George and colleagues, the biological model “was universally well received by perpetrators and contributed to both a reduction in their need to project blame and a willingness to assume respon- sibility for their behavior and participate in IPV treatment.” Although combination treatment with fluoxetine, CBT, and alcohol counseling appeared to reduce aggression signifi- cantly, the degree to which the individual treatments contributed to reductions in physical and nonphysical improvements is not clear. A study with a much larger sample and a different design would be needed to determine the degree to which each of these factors contributed to reduc- tions in aggressive behaviors. The authors report that new studies are underway using functional magnetic resonance imaging to assess fluoxetine’s effects on brain function. The authors report no funding, support, or potential conflicts of interest.  • • • • • • • • • • • • • • • • • • • • • • • • • • • • George DT, Phillips MJ, Lifschitz M, et al.: Fluox- etine treatment of alcoholic perpetrators of domestic violence: A 12-week, double-blind, randomized, placebo-controlled intervention study. J Clin Psy- chiatry 2010 June 29. E-pub ahead of print: DOI: 10.4088/JCP.09m05256gry. E-mail: [email protected]. Re f e Re n c e s 1. Trial registration: ClinicalTrials.gov identifier:

NCT00011765. Full description (last updated on June 4, 2010) at http://clinicaltrials-lhc.nlm.nih.gov/ ct2/show/NCT00011765. 2. George DT, et al.: Biol Psychiatry 2000; 47(9):804–812. Commentary by lead author David T. George, M.D. This study adds to a growing literature indicating that there is a biological compo- nent to domestic violence. This is important for a number of reasons. First, it places responsibility on the medical community to identify and assist in the treatment of per - petrators of domestic violence just like they would for patients with other biological illnesses such as diabetes or hypertension. Second, presenting the biologically based medical model to the perpetrators pro- vides a nonthreatening means to confront their behavior and help them understand their overreactivity to perceived threats. The model contributes to both a reduction in the perpetrators’ need to project blame, and a willingness to assume responsibility for their behavior and participate in treatment. Third, by addressing the perpetrators’ alcohol consumption in conjunction with the administration of Prozac (or presumably other SSRIs), physicians can significantly im- pact the problem of domestic violence by decreasing the perpetrators’ anger and thus affording them a longer “fuse” before reacting to environmental stimuli. Fourth, these results, if confirmed in larger studies, provide evidence that treatment can impact this major societal problem. ▪ • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • David T. George, M.D., is a psychiatrist at the Laboratory of Clinical and Translational Studies, Na- tional Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland. n e W s n o t e s Escitalopram for treatment- resistant GAD Escitalopram may be an acceptable and potentially efficacious treatment for patients with generalized anxiety disorder (GAD) who still have clinically significant symp- toms following cognitive behavioral therapy (CBT), according to an open-label pilot study. Twenty-four patients with moderate severity of GAD were initially treated with CBT, 15 of whom completed ≥12 sessions.

During the CBT phase, there were sig- nificant improvements in GAD, depression, and quality of life. However, 8 completers of CBT continued to experience clinically significant anxiety, 7 of whom started esci- talopram treatment. At endpoint, the esci- talopram dose was 10 mg/day for 5 patients, and 20 mg/day for 2 patients. Four patients completed 12 weeks of escitalopram treat- ment, and 3 discontinued. There was a trend towards improvement with escitalopram in GAD symptoms on the Hamilton Rating Scale for Anxiety (HRSA) but no significant change on the self-rated Penn State Worry Questionnaire. Significant changes also oc- curred in GAD severity on secondary mea- sures, and all 4 completers showed a 50% reduction in HRSA score. However, without a placebo group for comparison, “we cannot rule out the possibility that improvement during escitalopram treatment was attribut- able to delayed benefits from (completed) CBT or nonspecific effects,” the authors write. Side effects leading to discontinua- tion were nausea, increased anxiety, insom- nia, tremor, gastrointestinal symptoms, ner - vousness, and irritability. Controlled studies with larger sample sizes are needed to determine escitalopram efficacy in patients with persistent GAD symptoms following CBT. [Schneier FR, et al.: J Nerv Ment Dis 2010; 198(6):458–461.] Lamotrigine effective for borderline personality disorder A preliminary study suggests that the anticonvulsant lamotrigine may be effec- tive in treating affective instability in pa- tients with borderline personality disorder (BPD). The study randomized 28 patients with DSM-IV BPD to treatment with flex- ibly dosed lamotrigine (N=15) or placebo (N=13) under double-blind conditions for 12 weeks. Seventeen patients (9 lamotri- gine) completed 12 weeks of treatment, and 23 patients (12 lamotrigine) completed 6 weeks. Lamotrigine-treated patients had significantly greater reductions in total Af- fective Lability Scale scores (p<0.05) and in scores on the affective instability item of the Zanarini Rating Scale (ZAN) for BPD (p<0.05) compared with placebo-treated pa- tients. A secondary outcome showed signifi- cantly greater reductions with lamotrigine in impulsivity scores on the ZAN-BPD versus placebo (p=0.001). “To our knowledge, our study is the first to show prospectively that any mood-stabilizing anticonvulsants can effectively treat overall affective in- stability in BPD,” the authors write. The findings are consistent with the only previ- ous study of pharmacotherapy of affective instability in BPD, in which fluvoxamine was modestly effective in reducing affective instability as measured by the Borderline Personality Disorder Severity Index. The 8 T h e Br o w n Un i v e r s iTy Ps y c h o Ph a r m a c o l o g y UPd a Te o c To Be r 2010 c a s e r e p o r t Delirium following addition of adjunctive quetiapine/valproate in BP Case 1: Female, 53 years old Medications: Lithium (Eskalith), sodium valproate, sertraline (Zoloft), quetiapine (Seroquel), haloperidol (Haldol) Comment: A 53-year-old woman with bipolar disorder since age 16, developed permanent mild renal insufficiency following acute lithium intoxication resulting from intentional over - doses 1 year prior to presentation. Valproate was started but despite good compliance she was hospitalized due to ongoing depression. One week after starting valproate 500 mg/day and sertraline 50 mg/day she experienced a manic episode, and sertraline was discontinued. Due to increasing mood instability, valproate was titrated to 1000 mg/day over the next 10 days with adjunctive quetiapine 100 mg/day. The night following quetiapine initiation, she devel- oped visual hallucinations with disorientation, confusion, agitation, and met DSM-IV criteria for delirium. Her valproate plasma level was 103 μg/ml. Results of neurologic, physical, and laboratory tests were normal. Within 2 days of discontinuing quetiapine, her delirium was fully resolved, with the addition of oral haloperidol 5 mg/day, although mania persisted.

Case 2: Male, 63 years old Medications: Lithium (Eskalith), quetiapine (Seroquel), sodium valproate Comment: A 63-year-old man with bipolar disorder since age 33, experienced acute lithium intoxication 5 years previously with concomitant use of a diuretic for hypertension and spo- radic use of lithium, resulting in mild renal insufficiency. He was prescribed valproate, which he took irregularly, and was eventually hospitalized for hyperactivity, irritability, pressure of speech, and aggression, and given a diagnosis of bipolar disorder, manic episode. For the next 3 weeks, he received valproate 1000 mg/day and quetiapine titrated up to 300 mg/day. Que- tiapine at 300 mg resulted in confusion and visual hallucinations, and delirium was diagnosed.

His plasma valproate level was 43 μg/ml. Consistent with delirium, an electroencephalogram showed diffuse background-slowing. Computerized axial tomography showed no abnormal- ity. Within 1 week of discontinuing quetiapine his delirium was fully resolved. “Although seemingly rare, we report 2 patients with bipolar disorder who developed delirium when pre- scribed quetiapine as an adjunct to valproate for acute mania.” The development of delirium may have been the result of a synergistic effect of valproate and adjunctive quetiapine in the presence of mild renal sufficiency. Alternatively, the mild renal insufficiency that developed following lithium intoxication resulted in an accumulation of quetiapine. One study 1 has re- ported increased plasma quetiapine concentrations associated with older age, as well as a 77% increase in quetiapine plasma concentrations with concomitant use of valproate. Any or all of these factors may have induced anticholinergic delirium in the current cases. ▪ • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • Huang CC, Wei IH: Unexpected interaction between quetiapine and valproate in patients with bipolar disor - der. Gen Hosp Psychiatry 2010; 32(4):446.e1–446.e2. E-mail: [email protected].

Re f e Re n c e 1. Aichorn W, et al.: Influence of age, gender, body weight, and valproate comedication on quetiapine plasma concentrations. Int Clin Psychopharmacol 2006; 21:81–87. Safety alert for lamotrigine A safety alert for lamotrigine (Lamictal) was posted on August 12, warning that the drug can cause asep- tic meningitis. Lamotrigine is com- monly used for treating bipolar disor - der in adults, and seizures in children aged ≥2 years. Meningitis symptoms include headache, fever, stiff neck, nausea, vomiting, rash, and sensitiv- ity to light. Rapid diagnosis is needed to initiate prompt treatment. [www.

fda.gov/Safety/MedWatch/Safety Information/SafetyAlertsforHuman MedicalProducts/ucm222269.htm] Drug Safety Changes A list of drug safety labeling changes for June 2010 is available at www.fda.gov/Safety/MedWatch/ SafetyInformation/ucm218813.htm.

New Approvals A list of all original, tentative, and supplemental FDA approv- als for the month of July 2010 is available at www.accessdata.fda.

gov/scripts/cder/drugsatfda/index.

cfm?fuseaction=Reports.Monthly ApprovalsAll.

”Bad Ad” program The FDA’s “Bad Ad” program encourages healthcare providers to play a role in making sure “that prescription drug advertising and promotion is truthful and not mis- leading.” The program asks health- care providers to remain aware of the many ads and promotions they see everyday, and to help stop FDA violations by reporting activities and messages that they consider to be false or misleading. [Further details are available at www.fda.gov/Drugs/ GuidanceComplianceRegulatory Information/Surveillance/Drug MarketingAdvertisingandCommuni cations/ucm209384.htm.] FDA From the n e W s n o t e s authors recommend that future studies in- vestigating lamotrigine in this population be designed with longer treatment dura- tion, larger sample sizes, more severely ill borderline patients including those who are actively suicidal, and provide more infor - mation on lamotrigine’s effectiveness for affective instability in male BPD patients.

[Reich DB, et al.: Int Clin Psychopharmacol 2010. E-pub ahead of print: DOI: 10.1097/ YIC.0b013e32832d6c2f] continued from previous page Copyright of Brown University Psychopharmacology Update is the property of John Wiley & Sons, Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.