Practice patterns of bupropion co-prescription with antipsychotic medications.

Objective: Bupropion is one of the few medications with an FDA indication for smoking cessation. This is of particular significance due to the high co-morbidity of tobacco use disorder in patients with schizophrenia spectrum and other psychotic disorders. We sought to determine whether historical suggestions of bupropion's pro-dopaminergic activity lead prescribers to withhold bupropion in populations receiving antipsychotic medications. Methods: The prevalence in clinical practice of the combination of bupropion and 10 antipsychotic formulations was determined by a computer review of the Genoa Healthcare database for all prescribers at 10 participating community mental health centers. Actual prevalence was compared with expected prevalence using the test of proportions. A Bonferroni correction for multiple comparisons was included. Results: Clozapine, p = 0.0004, and the microsphere formulation of risperidone, p = 0.0045, were prescribed with bupropion significantly less often that chance. None of the other eight antipsychotic formulations were prescribed significantly differently than chance. Conclusions: The co-prescription of bupropion and antipsychotic medication may be affected by historical misconceptions regarding bupropion's purportedly pro-dopamine properties. Viable options for the treatment of tobacco use disorder should not be discounted prematurely in patients with schizophrenia spectrum and other psychotic disorders. We suggest further study on the safety and efficacy of the combination of bupropion and antipsychotic medication is needed.

Prevalence and socioeconomic factors in the prescription of concurrent amphetamine and alprazolam.

OBJECTIVE: Goals were to determine the prevalence of concurrent prescription of amphetamine and alprazolam, and examine variation by socioeconomic factors. METHODS: Washington State's Prescription Monitoring Program was reviewed for calendar years 2013 through 2017. Individuals receiving more than 180 days of amphetamine, alprazolam or both were tabulated for each zip code. Prescription rates were compared between zip codes with variation in rural/urban setting and fraction of low and high income households using a multiple regression. RESULTS: One in 3920 individuals in the general population of Washington State were taking a combination of alprazolam and amphetamine. The statewide prevalence of this combination increased 40.2% between 2013 and 2017. The prevalence of the combination in each zip code is significantly positively correlated with the fraction of high income households, p < 0.001, and urban area, p < 0.05. In contrast, the prevalence of amphetamine increased with both the fraction of high income, p < 0.001, and low income households, p < 0.01, with an incremental increase over twice as large with fraction of high income (b = 232 (25)) than low income households (b = 102 (38)). In contrast, alprazolam decreased in prevalence with the fraction of high income households, p < 0.05. CONCLUSIONS: The prevalence of concurrent prescription of alprazolam and amphetamine correlates with local socioeconomic factors, including greater household income, instead of the prevalence of FDA indications, including anxiety disorders or ADHD. More clinical studies are required to establish efficacy and guidelines for safe use to mitigate the increased risk of accidents in patients taking concurrent amphetamine and alprazolam.

Relative prevalence of 10 types of pharmacodynamic interactions in psychiatric treatment.

Objective: To assess the relative prevalence and factors affecting the prescription of medication combinations with a theoretical efficacy limiting pharmacodynamic interaction, defined as two medications with opposing indications and side effects or antagonistic action at the primary receptor of mechanism of action. Method: One hundred sixteen combinations were identified for 10 types of pharmacodynamic interactions. PubMed was searched for each combination to assess the quality of evidence either supporting clinical use or verifying reduced efficacy. Micromedex was searched to determine the presence of warnings to prescribers of reduced efficacy. The prevalence in clinical practice was determined by computer review of the Genoa Healthcare database for all prescribers at 10 participating community mental health centers. The expected prevalence was calculated as the product of the probability of each medication prescribed alone and was compared with the actual prevalence of the combination using the test of proportions. Results: The frequency of prescription of eight combinations met the Bonferroni corrected level of significance of p < 0.001. Four were combinations of amphetamine and D2 antagonists and each were prescribed less often than chance, p = 0.0001 consistent with epidemiological studies and multiple animal studies verifying an efficacy limiting interaction. Despite epidemiological studies indicating increased risk of accidents, alprazolam and amphetamine were prescribed more often than chance, p = 0.0001. Micromedex generated warnings for efficacy limiting interactions for five other combinations, but with no subsequent change in prescription frequency. Conclusions: Neither presence of medical evidence nor warnings from Micromedex consistently affect the prescription of combinations with pharmacodynamic efficacy limiting interactions.

Hotel Room Suicide: Cuyahoga, Orange, Travis, and Wayne Counties.

OBJECTIVE: To compare the suicide rates of local residents registering in local hotels with the general suicide rate in that county and to compare the suicide rates of hotel guests from outside the county with the national suicide rate. METHODS: The numbers of cases of suicide in hotel rooms and the general community were tabulated for Cuyahoga County, Ohio, for calendar years 2010-2017; in Orange County, California, and Travis County, Texas, for 2010-2012; and in Wayne County, Michigan, for 1997 to March 2005. The percentage of local residents registering in local hotel rooms was estimated from various sources to stratify the suicide risk for travelers and local residents. RESULTS: The suicide rate of local residents registering in local hotels was elevated compared to the general nonhotel population in each county (range of relative risk, 15.1-37.8; P < .0001, Poisson distribution). Hotel guests from outside each county had a reduced rate of suicide compared to the national rate (range of relative risk, 0.124-0.524; P < .05, Poisson distribution). With regard to suicide method, drug overdoses accounted for a significantly greater percentage in hotel rooms than in the nonhotel population in 3 of 4 counties (range of risk ratios, 2.03-4.51, P < .01; test of proportions), with the opposite pattern for gunshot wounds (range of risk ratios, 0.27-0.50; P < .01, test of proportions). CONCLUSIONS: Although local residents register in hotels for various reasons, there appears to be a subpopulation with a purpose of avoiding rescue. Consistent with the risk-rescue rating, means of suicide with lower lethality, eg, drug overdoses, account for a greater percentage of cases in a setting with less chance of rescue. In contrast to the local use population, the sense of purpose or meaning inherent in travel could explain the decreased risk of suicide in guests from outside the county.

Transcranial magnetic stimulation in the treatment of chronic widespread pain: a randomized controlled study.

OBJECTIVE: Our objective was to assess transcranial magnetic stimulation (TMS) in the treatment of chronic widespread pain. METHODS: Nineteen participants were randomized into 2 groups: one group receiving active TMS (n = 7) and another group receiving sham stimulation (n = 11) applied to the left dorsolateral prefrontal cortex. During sham stimulation, subjects heard a sound similar to the sound heard by those receiving the active treatment and received an active electrical stimulus to the scalp. The stimulation protocol consisted of 15 sessions completed within a 4-week period. Blind assessments were done at baseline and after each 5 sessions followed by blind assessments at 1 week, 1 month, and 3 months after the last TMS sessions. The primary outcome variable was a pain measure, the Gracely Box Intensity Scale (BIRS). RESULTS: The percentage of subjects who guessed that they were receiving TMS was similar in the 2 groups. Both the TMS group and the sham group showed a statistically significant reduction in the BIRS scores from baseline during the acute phase of treatment and the follow-up phase. However, the TMS and sham groups did not differ in the change in the BIRS scores. DISCUSSION: Although some previous clinical studies and basic science studies of TMS in treating pain are promising, this study found no difference in the analgesic effect of TMS and sham stimulation. Future studies should use a sham condition that attempts to simulate the sound and sensation of the TMS stimulation. Stimulus location and other stimulus parameters should be explored in future studies.

Baseline and treatment-emergent EEG biomarkers of antidepressant medication response do not predict response to repetitive transcranial magnetic stimulation.

There has been a surge of interest in biomarkers that can rapidly predict or assess response to psychiatric treatment, as the current standard practice of extended therapeutic trials is often dissatisfying to both clinicians and patients. Electroencephalographic (EEG) biomarkers in particular have been proposed as an inexpensive yet rapid way of determining whether a patient is responding to an intervention, usually before subjective mood improvement occurs. However, even the most well-reported EEG algorithms have not been subjected to independent replication, limiting their clinical generalizability. It is also unclear whether those biomarkers can generalize beyond their original study population, e.g. to patients undergoing somatic treatments for depression. We report here analysis of EEG data from the pivotal OPT-TMS study of transcranial magnetic stimulation (rTMS) for major depressive disorder. In this dataset, previously reported biomarkers of medication response showed no significant correlation with eventual response to rTMS treatment. Furthermore, EEG power in multiple bands measured at baseline and throughout the treatment course did not correlate with or predict either binary (response/nonresponse) or continuous (Hamilton Rating Scale for Depression) outcome measures. While somewhat limited by technical difficulties in data collection, these analyses are adequately powered to detect clinically relevant biomarkers. We believe this highlights a need for wider-scale independent replication of previous EEG biomarkers, both in pharmacotherapy and neuromodulation.

Improving the antidepressant efficacy of transcranial magnetic stimulation: maximizing the number of stimulations and treatment location in treatment-resistant depression.

OBJECTIVE: To assess the efficacy of increasing the number of fast left repetitive transcranial magnetic stimulations (rTMS) (10 Hz @ 120% of motor threshold (MT) over the left dorsolateral prefrontal cortex (DLPFC)) needed to achieve remission in treatment-resistant depression (TRD). And, to determine if patients who do not remit to fast left will remit using slow right rTMS (1 Hz @ 120% MT over the right DLPFC). METHOD: Patients were part of a multicenter sham-controlled trial investigating the efficacy of fast left rTMS. Patients who failed to meet minimal response criteria in the sham-controlled study could enroll in this open fast left rTMS study for an additional 3-6 weeks. Patients who failed to remit to fast left could switch to slow right rTMS for up to 4 additional weeks. The final outcome measure was remission, defined as a HAM-D score of <3 or 2 consecutive HAM-D scores less than 10. RESULTS: Forty-three of 141 (30.5%) patients who enrolled in the open phase study eventually met criteria for remission. Patients who remitted during fast left treatment received a mean of 26 active treatments (90,000 pulses). Twenty-six percent of patients who failed fast left remitted during slow right treatment. CONCLUSION: The total number of rTMS stimulations needed to achieve remission in TRD may be higher than is used in most studies. TRD patients who do not respond to fast left rTMS may remit to slow right rTMS or additional rTMS stimulations.

Daily left prefrontal transcranial magnetic stimulation therapy for major depressive disorder: a sham-controlled randomized trial.

CONTEXT: Daily left prefrontal repetitive transcranial magnetic stimulation (rTMS) has been studied as a potential treatment for depression, but previous work had mixed outcomes and did not adequately mask sham conditions. OBJECTIVE: To test whether daily left prefrontal rTMS safely and effectively treats major depressive disorder. DESIGN: Prospective, multisite, randomized, active sham-controlled (1:1 randomization), duration-adaptive design with 3 weeks of daily weekday treatment (fixed-dose phase) followed by continued blinded treatment for up to another 3 weeks in improvers. SETTING: Four US university hospital clinics. PATIENTS: Approximately 860 outpatients were screened, yielding 199 antidepressant drug-free patients with unipolar nonpsychotic major depressive disorder. INTERVENTION: We delivered rTMS to the left prefrontal cortex at 120% motor threshold (10 Hz, 4-second train duration, and 26-second intertrain interval) for 37.5 minutes (3000 pulses per session) using a figure-eight solid-core coil. Sham rTMS used a similar coil with a metal insert blocking the magnetic field and scalp electrodes that delivered matched somatosensory sensations. MAIN OUTCOME MEASURE: In the intention-to-treat sample (n = 190), remission rates were compared for the 2 treatment arms using logistic regression and controlling for site, treatment resistance, age, and duration of the current depressive episode. RESULTS: Patients, treaters, and raters were effectively masked. Minimal adverse effects did not differ by treatment arm, with an 88% retention rate (90% sham and 86% active). Primary efficacy analysis revealed a significant effect of treatment on the proportion of remitters (14.1% active rTMS and 5.1% sham) (P = .02). The odds of attaining remission were 4.2 times greater with active rTMS than with sham (95% confidence interval, 1.32-13.24). The number needed to treat was 12. Most remitters had low antidepressant treatment resistance. Almost 30% of patients remitted in the open-label follow-up (30.2% originally active and 29.6% sham). CONCLUSION: Daily left prefrontal rTMS as monotherapy produced statistically significant and clinically meaningful antidepressant therapeutic effects greater than sham. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00149838.

Hemispheric asymmetry in resting motor threshold in major depression.

OBJECTIVES: Previous studies of repetitive transcranial magnetic stimulation suggest a hemispheric imbalance in patients with major depression. These studies report an antidepressant effect by activation of the left prefrontal cortex or inhibition of the right prefrontal cortex. The aim of this study is to investigate interhemispheric differences in cortical excitability in a large sample of patients with major depression. METHODS: The resting motor threshold (RMT) was measured on 91 patients with treatment-resistant major depression. We controlled for current medication use, gender, age, handedness, and study site. RESULTS: There was no significant difference between the left RMT (55.96 [10.356]) and the right (57.74 [11.359]) (P = 0.131, Wilcoxon matched-pairs test). A multivariate analysis found no significant association between depression scores and right or left RMT. After adjusting for important cofactors, benzodiazepine use was found to be a significant predictor of left RMT (P = 0.017, linear regression) and right RMT (P = 0.007, linear regression). CONCLUSION: Our results do not support the existence of an interhemispheric imbalance of cortical excitability in depressed patients. Benzodiazepine use was found to raise both the left and right RMT.

The effect of daily prefrontal repetitive transcranial magnetic stimulation over several weeks on resting motor threshold.

BACKGROUND: The resting motor threshold (rMT) is an important factor in the selection of treatment intensity for patients receiving repetitive transcranial magnetic stimulation (rTMS). In many clinical studies to date, due to concerns about potential drift, the rMT has been routinely re-measured weekly or every fifth session. OBJECTIVE: Our aim is to investigate whether ongoing treatment with rTMS affects the rMT, the degree of change, and whether frequent remeasurement is needed. METHODS: Clinical data were drawn from 50 medication free patients receiving treatment for major depression with rTMS in a large U.S. NIH-sponsored multisite study. Four measurements of rMT were obtained including before and after the double blind phase, followed by weekly measurements during the open phase. Active treatment consisted of 75 four second trains of 10Hz stimulation applied over 37.5 minutes with the coil over the left DLPFC at 120% rMT. RESULTS: For the group as a whole, there was no significant change in the rMT during a minimum of 2 weeks of treatment with prefrontal rTMS (p=0.911, one way ANOVA). The average within-subject coefficient of variation was 6.58%. On average the last rMT was 2.45% less than the baseline rMT (range 32.3% increase, 40.6% decrease). CONCLUSION: Daily left prefrontal rTMS over several weeks as delivered in this trial does not cause systematic changes in rMT. While most subjects had <10% variance in rMT over time, 5 subjects had changes of approximately 20% from baseline, raising dosing and safety issues if undetected. We recommend that clinical trials of rTMS have periodic retesting of rMT, especially if the dose is at or near the edge of the TMS safety tables.

Hotel room suicide: Las Vegas and Clark County.

Our objective is to study the link between hotel registration and suicide. Clark County, which contains Las Vegas, drew our interest because of its extremely large number of hotel rooms. Case files of suicide from the Clark County Coroner were reviewed for years 2003-2005. The suicide rate of local residents registering in local hotels was 271/100,000. This is greater than the suicide rate in the general population of Clark County, 16.6/100,000, P<0.0001, Poisson distribution. Hotel guests from outside Clark County had a reduced rate of suicide, 4.6/100,000, P<0.0001. Residents of Clark County registering in local hotels have an increased suicide risk that is statistically significant. Possible explanations for the results are provided.

Validation of a rational malingering test using evoked potentials.

Malingering is easy to define, difficult to detect, and very costly for any health care system. The structured interview of reported symptoms (SIRS) was constructed using rational strategies to detect malingering in patients endorsing psychotic symptoms. This study validated the SIRS using evoked potentials. Nineteen patients meeting DSM-IV criteria for schizophrenia and 15 healthy controls completed an oddball and paired click protocol. Severity of psychotic symptoms was documented using the Scale for the Assessment of Negative Symptoms and the Scale for the Assessment of Positive Symptoms. The patient group was divided by probability of malingering according to the SIRS. Patients with a high probability of malingering had significantly greater P3 amplitude (P = 0.006, t-test) and more P50 suppression (P = 0.044, t-test) than patients with a low probability of malingering. No significant difference in P3 amplitude or P50 suppression was found between the patients with a high probability of malingering and the healthy controls. This study provides empirical support for the validity of the SIRS with evidence that is independent of patient report.

"Excessive tears": a diagnostic sign for cocaine-induced mood disorder?

OBJECTIVE: This study aims to investigate excessive tearfulness as a sign to help determine the etiology of depressive symptoms. METHODS: Clinicians were instructed to document the occurrence of excessive tearfulness in all patients seen in the Psychiatric Emergency Service. Excessive tearfulness was defined as crying to the severity that at least 1 tear drops off the face. A comparison group was formed from the general population of the Psychiatric Emergency Service. RESULTS: Excessive tearfulness was documented in 36 different patients. The prevalence of the sign in the general population was 1.9%. Patients with excessive tearfulness were more likely to have cocaine in their urine (P < .0001, chi(2) test), receive a substance-related primary diagnosis (P < .0001, chi(2) test), and be admitted for psychiatric hospitalization (P < .001 chi(2) test). Patients with excessive tearfulness had significantly shorter voluntary hospital stays (P < .05, t test). CONCLUSION: Excessive tearfulness could be a useful clinical sign of cocaine-induced depression.

Carisoprodol withdrawal induced delirium: A case study.

A 43-year-old woman with chronic back pain found relief by taking carisoprodol, a centrally acting skeletal muscle relaxant. She had acquired large amounts of the prescription medication through the Internet and was taking approximately three hundred 350 mg tablets each week, at times up to fifty tablets per day. She then abruptly stopped the medication and presented to the emergency room one week later with waxing and waning attention, confusion, disorientation and visual hallucinations. Oral lorazepam was dosed according to a protocol employing the Clinical Institute Withdrawal Assessment of Alcohol Scale (CIWA). Her symptoms of delirium resolved rapidly and she was discharged home on day three. A review of the literature did not show any other reports of carisoprodol withdrawal induced delirium. Such withdrawal symptoms could be expected as the mechanism of action of carisoprodol is similar to that of hypnotic sedatives. Its availability and ease with which it can be acquired through the Internet puts it at great risk for a drug of abuse.

Hotel room suicide.

The objective of our research was to quantify the increased risk of suicide associated with registering in local hotels/motels. Medical examiner case files of suicide in King County, Washington, were reviewed for years 2002-2004. The incidence of suicide in local residents registering in local hotels/motels was 223/100,000 which is significantly greater than the incidence of suicide in the general population of King County (11.7/100,000 p < 0.0001). Hotel/motel guests from outside Washington had a significantly reduced incidence of suicide (3.9/100,000 p = 0.002). The study results suggest that there is an increased risk of suicide in local residents who register in local hotel rooms.