Hypertensive Emergency Secondary to Combining Psilocybin Mushrooms, Extended Release Dextroamphetamine-Amphetamine, and Tranylcypromine.

Data on medication interactions with psychedelics are limited. Here we present what may be the first published report of a hypertensive emergency following the combination of psilocybin mushrooms with a monoamine oxidase inhibitor (MAOI). A 42-year-old man with treatment-resistant major depressive disorder took 1 g of Psilocybe cubensis mushrooms, while prescribed tranylcypromine, extended-release dextroamphetamine-amphetamine, and other medications. Approximately half an hour later, he developed severe hypertension with chest pain, palpitations, and headache. Upon hospital presentation, the electrocardiogram demonstrated ST-elevation. The patient was diagnosed with a myocardial infarction and treated with lorazepam, nitroglycerin, and aspirin. He subsequently underwent emergency cardiac catheterization, which revealed no significant cardiac abnormalities. Following overnight hospitalization, he was discharged home with no lasting physical sequelae. Though data are few, past studies suggest that classic serotonergic psychedelics (5HT-2A receptor agonists) such as dimethyltryptamine (DMT), lysergic acid (LSD), and synthetic psilocybin should not produce hypertensive emergency when combined with MAOIs. We suspect phenylethylamine, found in Psilocybe cubensis and other species of psilocybin mushrooms, interacted with tranylcypromine and dextroamphetamine-amphetamine to produce this hypertensive emergency. Patients prescribed MAOIs should be warned of the potential for hypertensive emergency when consuming psilocybin mushrooms, particularly when also prescribed norepinephrine releasers such as dextroamphetamine-amphetamine.

A Survey of American Psychiatrists Concerning Medication Prior Authorization Requirements.

This study examined opinions of American psychiatrists regarding prior authorization (PA) requirements for third-party payer coverage of medications and quantified perceived impact of these requirements on clinical practice. One thousand selected psychiatrist members of the American Psychiatric Association were invited to participate in a survey. Response rate was 33.1%. Respondents predominantly believed the obligation to obtain PA reduces job satisfaction and negatively impacts patient care. A total of 59.9% of respondents reported employing either diagnosis modification or falsification of previous medication trials at least occasionally in order to obtain PA. A total of 66.6% refrained at least occasionally from prescribing preferred medications due to PA requirement or expectation of one. On multivariate analysis, risk factors for refraining at higher frequency included seeing 300 or more patients in the previous 3 months, engaging more frequently in diagnosis modification, and reporting increased perception that obtaining PA reduces time for patient care.

Targeted Treatment of Individuals With Psychosis Carrying a Copy Number Variant Containing a Genomic Triplication of the Glycine Decarboxylase Gene.

BACKGROUND: The increased mutational burden for rare structural genomic variants in schizophrenia and other neurodevelopmental disorders has so far not yielded therapies targeting the biological effects of specific mutations. We identified two carriers (mother and son) of a triplication of the gene encoding glycine decarboxylase, GLDC, presumably resulting in reduced availability of the N-methyl-D-aspartate receptor coagonists glycine and D-serine and N-methyl-D-aspartate receptor hypofunction. Both carriers had a diagnosis of a psychotic disorder. METHODS: We carried out two double-blind, placebo-controlled clinical trials of N-methyl-D-aspartate receptor augmentation of psychotropic drug treatment in these two individuals. Glycine was used in the first clinical trial, and D-cycloserine was used in the second one. RESULTS: Glycine or D-cycloserine augmentation of psychotropic drug treatment each improved psychotic and mood symptoms in placebo-controlled trials. CONCLUSIONS: These results provide two independent proof-of-principle demonstrations of symptom relief by targeting a specific genotype and explicitly link an individual mutation to the pathophysiology of psychosis and treatment response.

Results from a long-term open-label extension study of adjunctive buprenorphine/samidorphan combination in patients with major depressive disorder.

Buprenorphine/samidorphan (BUP/SAM; ALKS 5461) is an investigational opioid system modulator for the adjunctive treatment of patients with major depressive disorder (MDD), who did not respond adequately to prior antidepressant therapy (ADT). FORWARD-2, an open-label extension study, assessed long-term safety and tolerability of adjunctive BUP/SAM treatment in these patients. Patients from four short-term trials and de novo patients were enrolled; all had confirmed MDD and a current major depressive episode lasting 2-24 months. Patients were treated with an established ADT for ≥8 weeks before receiving sublingual, adjunctive BUP/SAM 2 mg/2 mg for up to 52 weeks. Safety (primary objective) was assessed via adverse events (AEs), the Columbia-Suicide Severity Rating Scale, and the Clinical Opiate Withdrawal Scale (COWS). Exploratory evaluation of efficacy was done using the Montgomery-Åsberg Depression Rating Scale (MADRS). Of 1485 patients, 50% completed the study and 11% discontinued due to AEs. AEs of nausea, headache, constipation, dizziness, and somnolence, each occurred in ≥10% of patients. There was no evidence of increased suicidal ideation or behavior. Euphoria-related AEs were uncommon (1.2%). Following abrupt BUP/SAM discontinuation, "drug withdrawal" AEs were infrequent (0.4%), and the incidence of COWS categorical worsening after abrupt drug discontinuation was low (6.5%). Improvements in mean MADRS scores were maintained until study end, suggesting durability of antidepressant effect in patients continuing treatment. BUP/SAM was generally well tolerated, with a low risk of abuse and an AE profile consistent with those seen in placebo-controlled studies. Withdrawal reports were uncommon and of limited clinical impact.

Opioidergic Agents as Antidepressants: Rationale and Promise.

Research concerning psychiatric issues relating to opioid drugs currently focuses primarily on their role in reinforcing addictive behaviors, given the recent proliferation of lethal abuse of illicit opiates in the United States and around the world. In contrast, this article will review the mechanism of action of opioids in affective disorders and the available evidence and potential for their use, especially in the treatment of resistant major depression. Buprenorphine is the opioid derivative of special interest; we review this and other opioid derivatives, highlighting the growing role of opioids in treating depressive illnesses and other related psychopathologies.

Thought Disorder in Schizophrenia and Bipolar Disorder Probands, Their Relatives, and Nonpsychiatric Controls.

Thought disorder (TD) has long been associated with schizophrenia (SZ) and is now widely recognized as a symptom of mania and other psychotic disorders as well. Previous studies have suggested that the TD found in the clinically unaffected relatives of SZ, schizoaffective and bipolar probands is qualitatively similar to that found in the probands themselves. Here, we examine which quantitative measures of TD optimize the distinction between patients with diagnoses of SZ and bipolar disorder with psychotic features (BP) from nonpsychiatric controls (NC) and from each other. In addition, we investigate whether these same TD measures also distinguish their respective clinically unaffected relatives (RelSZ, RelBP) from controls as well as from each other. We find that deviant verbalizations are significantly associated with SZ and are co-familial in clinically unaffected RelSZ, but are dissociated from, and are not co-familial for, BP disorder. In contrast, combinatory thinking was nonspecifically associated with psychosis, but did not aggregate in either group of relatives. These results provide further support for the usefulness of TD for identifying potential non-penetrant carriers of SZ-risk genes, in turn enhancing the power of genetic analyses. These findings also suggest that further refinement of the TD phenotype may be needed in order to be suitable for use in genetic studies of bipolar disorder.

Opioid Modulation With Buprenorphine/Samidorphan as Adjunctive Treatment for Inadequate Response to Antidepressants: A Randomized Double-Blind Placebo-Controlled Trial.

OBJECTIVE: Major depressive disorder has been associated with dysregulation of the endogenous opioid system. The authors sought to determine whether opioid modulation achieved through administration of ALKS 5461, a combination of a µ- and κ-opioid partial agonist, buprenorphine, and a µ-opioid antagonist, samidorphan, would exhibit antidepressant activity in patients with major depression. METHOD: A multicenter, randomized, double-blind, placebo-controlled, two-stage sequential parallel comparison design study was conducted in adults with major depression who had an inadequate response to one or two courses of antidepressant treatment. Participants were randomly assigned to receive adjunctive treatment with 2 mg/2 mg of buprenorphine/samidorphan (the 2/2 dosage group), 8 mg/8 mg of buprenorphine/samidorphan (the 8/8 dosage group), or placebo. Antidepressant effect was measured based on change from baseline to the end of 4 weeks of treatment on the 17-item Hamilton Depression Rating Scale (HAM-D), the Montgomery-Åsberg Depression Rating Scale (MADRS), and the Clinical Global Impressions severity scale (CGI-S). RESULTS: Compared with the placebo group, there were significantly greater improvements in the 2/2 dosage group across the three depression outcome measures (HAM-D: -2.8, 95% CI=-5.1, -0.6; MADRS: -4.9, 95% CI=-8.2, -1.6; CGI-S: -0.5, 95% CI=-0.9, -0.1). There was also evidence of improvement in the 8/8 dosage group, although it did not achieve statistical significance. Overall, the buprenorphine/samidorphan combinations were well tolerated, and there was no evidence of opioid withdrawal on treatment discontinuation. CONCLUSIONS: The buprenorphine/samidorphan combination is a novel and promising candidate for treatment of major depressive disorder in patients who have an inadequate response to standard antidepressants.

Quantitative Measures of Craniofacial Dysmorphology in a Family Study of Schizophrenia and Bipolar Illness.

Several laboratories, including ours, have reported an overrepresentation of craniofacial (CF) anomalies in schizophrenia (SZ). How might this dysmorphology arise in a brain-based disorder? Because the brain and face derive from shared embryologic primordia and morphogenetic forces, maldevelopmental processes may result in both CF and brain dysmorphology.Our approach is 2-pronged. First, we have employed, for the first time in the study of psychiatric disorders, objective measures of CF morphology that utilize an extensive normative database, permitting computation of standardized scores for each subject. Second, we have rendered these findings biologically interpretable by adopting principles of embryology in the analysis of dysmorphology.Dependent measures in this investigation focused on derivatives of specific embryonic primordia and were contrasted among probands with psychotic disorders, their first-degree relatives, and normal controls (NC). Subject groups included patients with a diagnosis of SZ (N = 39) or bipolar (BP) disorder with psychotic features (N = 32), their clinically unaffected relatives (N = 82 and N = 41, respectively), and NC (N = 95) subjects.Anomalies involving derivatives of frontonasal and mandibular embryonic primordia showed a clear association with psychotic illness, as well as familial aggregation in relatives in both diagnostic groups. In contrast, one class of CF anomalies emerged only among SZ probands and their first-degree relatives: dysmorphology arising along the junction of the frontonasal and maxillary prominence derivatives, manifested as marked asymmetries. This class was not overrepresented among the BP patients nor among their relatives, indicating that this dysmorphology appears to be specific to SZ and not a generalized feature of psychosis. We discuss these findings in light of embryologic models that relate brain regions to specific CF areas.

Safety of selegiline transdermal system in clinical practice: analysis of adverse events from postmarketing exposures.

OBJECTIVE: The objective of this analysis is to present the safety profile of selegiline transdermal system (STS) in clinical practice after US Food and Drug Administration approval by analyzing reported postmarketing adverse events (AEs). METHOD: Deidentified data were obtained on AEs, regardless of causality, as collected and compiled in the pharmaceutical company's adverse event collection systems/databases after the launch of STS in the United States. All reports of hypertensive crisis, suicide attempts, and STS overdoses were carefully examined to independently determine relation of the AE to STS. RESULTS: From April 2006 to October 2010, a total of 3,155 AEs in 1,516 patients were reported (5.2% of the total exposures; N = 29,141), regardless of causality. The most frequently reported categories of AEs were general disorders (no. of AEs = 1,037, 3.6%) and central nervous system (CNS) disorders (no. of AEs = 574, 2.0%). A total of 266 reports (0.9%) were classified as serious AEs; CNS disorders (no. of AEs = 71, 26.7%) and cardiac and vascular disorders (no. of AEs = 44, 16.5%) were most common. There were 13 self-reports of possible hypertensive events or hypertension, although objective clinical data were not submitted in any of these cases. Thirteen drug-drug interactions (0.04%) were reported, and 5 were classified as serious. CONCLUSIONS: The most commonly reported AEs were application site reactions and insomnia. Very few patients reported a hypertensive event, and there were no objectively confirmed reports of hypertensive crisis with food at any STS dose. Therapeutic doses of STS appear to have a safety profile in clinical practice that is consistent with that observed in clinical trials. However, given the relatively modest exposure numbers, continued safety monitoring is recommended.

Psychiatric treatment of the VIP: some paradoxical risks.

One might expect that VIPs-individuals with wealth, fame, or power-would typically receive excellent care when treated for psychiatric disorders. Often, this is the case, but paradoxically, VIP status may compromise the quality of psychiatric treatment. In this article, we present four case examples, representing disguised amalgamations of actual cases from our experience, demonstrating how VIP patients may sometimes receive suboptimal psychiatric care. These cases show certain similarities; typically, there was no serious doubt about the general nature of the treatment that should be undertaken, but the treatment team was unable to deliver that treatment in the usual manner because of various outside pressures created by the VIP status of the patient and by the patient's entourage. One possible solution to this problem, when feasible, is to assign treatment to a team specifically experienced with VIP patients. A strong and united treatment team, accustomed to the unusual difficulties and pressures often encountered with VIP patients, can be prepared to act promptly, firmly, and unanimously to devise an appropriate treatment plan and then maintain this plan true to its course despite these pressures.

Predictors of relapse in a study of duloxetine treatment for patients with generalized anxiety disorder.

OBJECTIVE: Data from a relapse prevention study of duloxetine treatment for adults with generalized anxiety disorder (GAD) were examined to identify predictors of relapse. METHODS: Patients responding to 6 months of open-label duloxetine treatment were randomized to continuation with duloxetine or withdrawal to placebo for a 6-month double-blind continuation phase (duloxetine, N= 216; placebo, N= 213). Post hoc analyses compared time to GAD relapse during continuation phase by using predictor variables that included patient demographics, symptom severity measures (Hamilton Anxiety Scale Scores [HAMA], Hospital Anxiety and Depression Scale), functional outcomes, and visual analogue scale (VAS) pain measures. Univariate and multivariate analyses were performed using predictor variables from time of randomization into the continuation, withdrawal phase. RESULTS: Severity of anxiety symptoms, degree of functional impairment, and severity of pain at time of randomization were significantly predictive of likelihood of relapse during the continuation phase. Multivariate backwards elimination analysis of significant univariate predictors identified HAMA item one (anxious mood) ≥ 1 and severity of pain while awake (≥ 30 on VAS) as the strongest predictors of GAD relapse. CONCLUSIONS: For patients with GAD responding to open-label treatment with duloxetine, residual symptoms related to anxious mood, pain severity, and psychosocial function were associated with increased relapse risk, although the greatest risk was associated with anxious mood and increased severity of pain while awake.

Transient receptor potential ankyrin 1: emerging pharmacology and indications for cardiovascular biology.

Transient receptor potential anykrin 1 (TRPA1) is a member of the TRP superfamily, representing the sole member of the TRPA subfamily. It has many identified endogenous and exogenous agonists, comprising largely of chemical irritants and products of oxidative stress. Classically located on sensory neurone endings, TRPA1 has developed a strong presence in pain and inflammatory studies, where it is now becoming an intriguing clinical drug target. TRPA1 is increasingly recognized in a growing number of neuronal and non-neuronal locations with expanding expression and activity profiles providing evidence of a role for TRPA1 in other systems. Interest in discovering the pharmacological and functional roles of TRPA1 is increasing and diversifying into many areas. Historically, compounds now known as TRPA1 agonists have demonstrated cardiovascular activity, modulating activities in both the heart and the vasculature. Now TRPA1 has been identified as the receptor via which these compounds can act, these studies are being revisited and expanded on using current techniques. It is therefore timely to review the current knowledge of TRPA1 receptor presence and activities of relevance to the cardiovascular system, summarizing findings to date and identifying potential areas for future investigation.

Tailoring the definition of the clinical schizophrenia phenotype in linkage studies.

The delineation of schizophrenia-related symptomatology is critical to informative clinical phenotyping in linkage studies. A minority of first-degree relatives of schizophrenia and schizoaffective probands (RelSZSA) qualifies for a clinical diagnosis in the schizophrenia spectrum. Schizotypal personality disorder (SPD) is a key component of this spectrum, largely because of its relatively specific familial aggregation in relatives. The criteria for SPD were not developed for the purpose of identifying RelSZSA, however, and SPD is not a homogeneous clinical disorder, potentially introducing false positives and false negatives into affectedness classifications. In this study we used logistic regression (LR) to identify the combination of clinical signs and symptoms that maximized the discrimination between nonpsychotic first-degree RelSZSA (n=241) and controls (n=161). Three variables contributed significantly to optimizing this distinction: no close friends or confidants other than family members, social isolation and irritability. The combination of deviant LR scores and schizophrenia-spectrum psychotic disorders had greater sensitivity for identifying RelSZSA, 23.7%, than SPD and schizophrenia-spectrum psychotic disorders, 16%. Importantly, the diagnosis of SPD and deviant LR scores were not significantly correlated. Most individuals with deviant LR scores did not meet criteria for a diagnosis of SPD and only a minority of those who were diagnosed with SPD had deviant LR scores. Since misclassification of gene carriers as non-gene carriers in linkage analyses increases the risk of false negatives, it may be advantageous to tailor the definition of the clinical phenotype to those aspects of social-interpersonal dysfunction that optimize the discrimination of RelSZSA from controls.

Modelling Staphylococcus aureus-induced septicemia using NMR.

We present a novel NMR-based study of the molecular aspects of the "attack" on human red blood cells (RBCs) by growing bacteria. Staphylococcus aureus expresses virulence factors, including alpha-hemolysin, which contribute to the clinical condition known as septic shock. alpha-Hemolysin is a pore-forming toxin and its secretion increases the permeability of a range of mammalian cell types infected with S. aureus. (31)P NMR spectra of the probe molecules dimethyl methylphosphonate (DMMP) and hypophosphite (HPA) in RBC suspensions show separate intra- and extracellular resonances. These resonances coalesced over time in RBC suspensions inoculated with S. aureus or pure alpha-hemolysin, due to increasing permeability of the RBC membrane. Increased RBC permeability resulted in leakage of intracellular proteins, plus an increase in the exchange rate of the solutes between the intra- and extracellular compartments, both effects contributing to the coalescence of the split peaks. The addition of antibiotics prevented peak coalescence and enabled the minimal inhibitory concentration (MIC) for eight strains of S. aureus to be determined for oxacillin and erythromycin. The MIC values obtained by using (31)P NMR spectroscopy were within one dilution of the MICs obtained using the standard National Committee for Clinical Laboratory Standards (NCCLS) method. The results are encouraging for the use of NMR spectroscopy in clinical microbiology.

Effect of caspofungin on metabolite profiles of Aspergillus species determined by nuclear magnetic resonance spectroscopy.

Invasive aspergillosis remains a potentially life-threatening infection, the incidence of which is increasing. Current methods used to determine the susceptibilities of Aspergillus strains to antifungal drugs are often unreliable. Nuclear magnetic resonance (NMR) spectroscopy can identify the metabolic complement of microorganisms while monitoring nutrient utilization from the incubation medium. We used 600-MHz (1)H NMR spectroscopy to monitor the metabolic responses of five Aspergillus species cultured in RPMI 1640-2% glucose-morpholinepropanesulfonate buffer to various concentrations of the antifungal drugs amphotericin B (AMB) and caspofungin. The metabolic endpoint (MEP) was determined from nutrient and metabolite resonances, measured as a function of the drug concentration, and was defined as a > or =50% reduction in nutrient consumption or metabolite production. MICs were evaluated by a modification of Clinical and Laboratory Standards Institute broth microdilution method M27-A, and minimal effective concentrations (MECs) were determined by microscopic examination of fungal hyphae. For AMB, the MEPs coincided with the MICs. For caspofungin, the MEPs agreed with the MECs for several Aspergillus strains, but the effect of drug pressure was more complex for others. Expansion of the MEP definition to include any significant changes in metabolite production resulted in agreement with the MEC in most cases. Paradoxical metabolic responses were observed for several Aspergillus strains at either high or low caspofungin concentrations and for one Aspergillus terreus strain with AMB. NMR spectroscopy proved to be a powerful tool for detecting the subtle effects of drug pressure on fungal metabolism and has the potential to provide an alternative method for determining the susceptibilities of Aspergillus species to antifungal drugs.

The price of a gift: an approach to receiving gifts from patients in psychiatric practice.

When a patient or patient's family presents a psychiatrist with a gift, the clinician is challenged to maintain appropriate professional boundaries but have the flexibility to respond with warmth and appreciation. The psychiatrist must consider such factors as the intention of the gift, its value to the patient, and the anticipated effect of accepting or refusing it on the patient and the treatment. Psychiatric practitioners are ethically obligated to consider patients' best interests when deciding about how to handle the offer of a gift. Ethical deliberations about such situations occur on a case-by-case basis and require careful analysis of how to promote the patient's best interest while adhering to professional ethics. In this article, members of the McLean Hospital Ethics Committee present a pragmatic model for managing the presentation of a gift from a patient or a patient's family member. The pragmatic model, which focuses on the practical results of accepting or declining the gift, minimizes the risk of exploiting the patient by accepting a gift or hurting the patient by declining it. We present five clinical cases that raise ethical dilemmas concerning patient gift giving in psychiatry and discuss each case from the standpoint of the pragmatic model.

Is PTSD caused by traumatic stress?

Sequential subjects (N=103) presenting for pharmacologic treatment of major depression were examined prior to treatment for history of traumatic experiences. Subjects were also examined for symptoms of posttraumatic stress disorder (PTSD). Two blinded raters subsequently judged whether subjects' experiences met DSM-IV criteria for trauma (criterion A of PTSD). Among 54 subjects scored by both raters as having experienced trauma, 42 (78%) met all other DSM-IV criteria for PTSD. Among 36 subjects scored by both raters as not having experienced trauma, 28 displayed all other DSM-IV criteria for PTSD--also a rate of 78%. This equivalence suggests that in a treatment-seeking population, caution should be exercised in attributing the PTSD syndrome to trauma.