Psilocybin for the Treatment of Obsessive-Compulsive Disorders.

Obsessive-compulsive disorder (OCD) is a highly prevalent and disabling condition for which currently available treatments are insufficiently effective and alternatives merit priority attention. Psilocybin may represent a safe and effective avenue for treatment of individuals affected by this condition. In this chapter we briefly introduce OCD symptoms, epidemiology, as well as relevant hypotheses on the mechanism of disease that may inform treatment interventions. We briefly describe currently available treatments, mechanisms of action, and efficacy limitations, as preamble to the potential use of psilocybin and perhaps similar compounds in the treatment of OCD and related conditions. Although much is reviewed throughout this book about the mechanisms of action of psychedelic agents, a focused discussion of psilocybin effects as they pertain to OCD is also included. Our experience with incidental observation, prospective research, and current explorations of psilocybin in OCD are also described.

Diversity and Inclusion in Psychiatry: The Pursuit of Health Equity.

The increasing diversity of America requires a workforce that is able to serve the mental health needs of individuals from multiple backgrounds, with a culturally proficient, inclusive, and affirming approach. To accomplish this, clinicians must be mindful of the multiple challenges presented by social determinants of mental health and access to care; the role of culture in wellness protection, mental illness expression, symptom attribution, and help seeking; the impact of provider factors, such as availability and cultural and linguistic congruence and proficiency; and the interaction of clinician and patient, who are with increasing frequency members of differing identity groups. The authors highlight the central role of clinical providers, academic institutions, and service organizations to advance health equity through training and commitment to increase high-quality services that are available, accessible, affordable, and acceptable, improving the care of all individuals.

Trauma-Informed Care and Cultural Humility in the Mental Health Care of People From Minoritized Communities.

The prevalence and impact of trauma constitute a public health crisis that is complicated by the cultural heterogeneity of contemporary society and a higher rate of trauma among individuals from minoritized communities. A trauma-informed care approach can facilitate improved treatment of those who have experienced trauma, and trauma-informed care is increasingly viewed as potentially beneficial for all patients. This article outlines general principles of trauma-informed care and ways to enact it. Because the situations in which trauma arises, the ways in which it is conceptualized, and how patients respond to it are influenced by both culture and individual factors, a cultural humility approach is also described and recommended. Psychiatrists can navigate the complex terrain of cultures and social backgrounds in the clinical encounter and can promote healing when treating patients who have experienced trauma by adopting a trauma-informed care approach and an attitude of cultural humility.

Affirmative Care Across Cultures: Broadening Application.

Affirmative practice is an approach to health and behavioral health care that validates and supports the identities stated or expressed by those served. Affirmative care requires the practitioner to actively honor and celebrate identity while at the same time validating the oppression felt by individuals seeking services. Validation and empathy fundamentally result from increased understanding of individuals' history, cultural context, and lived experiences. Origins of the approach honored the experience of those in LGBTQ+ communities; however, affirmative care should be valued across cultures, systems, and settings in which health and behavioral health care are offered. Affirmative care principles should be applied across cultures and communities while recognizing the worth of the individual and avoiding stereotyping. Along with delineating historical and demographic contexts, the authors offer recommendations for affirmative care in practice with African American, Asian, Indigenous, and Latinx individuals, as well as those living in rural communities.

Association Study of Genotype by Depressive Response during Tryptophan Depletion in Subjects Recovered from Major Depression.

PURPOSE: The brief and reversible mood response to acute tryptophan (TRP) depletion (ATD) is being studied as a trait marker in subjects considered at risk for major depression (MD). PROCEDURES: ATD was administered to 64 subjects (54 European-Americans, and10 from other races) with personal and family history of MD. They were in remission and had been medication-free for at least three months. Subjects received an active and sham condition in a random assignment, double-blind crossover design. They were genotyped for serotonin-related candidate genes, and mood response was quantified with the Hamilton Depression Rating Scale (HDRS). Data were analyzed using Poisson regression with repeated measures and latent trajectory models. RESULTS: Compared to the sham control, active ATD caused modest depressive changes showing significant main effects of test condition (χ2=5.14, df=1, p=0.023) and time (χ2=12.22, df=3, p=0.007), but no significant interaction of time and test condition. Latent trajectory analysis revealed two groups, identified as depletion responders and non-responders. Those with the HTR2A rs6313 CC genotype had significantly higher HDRS scores during ATD (χ2=11.72, df=1, p=.0006). CONCLUSIONS AND MESSAGE: ATD may help the identification of biological subtypes of MD. These data are consistent with imaging reports implicating 5-HT2A receptor function in ATD phenotypes.

Psychological distress following marital separation interacts with a polymorphism in the serotonin transporter gene to predict cardiac vagal control in the laboratory.

Marital separation is linked to negative mental and physical health; however, the strength of this link may vary across people. This study examined changes in respiratory sinus arrhythmia (RSA), used to assess cardiac vagal control, in recently separated adults (N = 79; M time since separation = 3.5 months). When reflecting on the separation, self-reported psychological distress following the separation interacted with a polymorphism in the serotonin transporter gene (5-HTTLPR) and a relevant single nucleotide polymorphism (SNP), rs25531, to predict RSA. Among people reporting emotional difficulties after the separation, those who were homozygous for the short allele had lower RSA levels while reflecting on their relationship than other genotypes. The findings, although limited by the relatively small sample size, are discussed in terms of how higher-sensitivity genotypes may interact with psychological responses to stress to alter physiology.

Vagus nerve stimulation therapy randomized to different amounts of electrical charge for treatment-resistant depression: acute and chronic effects.

BACKGROUND: Major depressive disorder is a prevalent, disabling, and often chronic or recurrent psychiatric condition. About 35% of patients fail to respond to conventional treatment approaches and are considered to have treatment-resistant depression (TRD). OBJECTIVE: We compared the safety and effectiveness of different stimulation levels of adjunctive vagus nerve stimulation (VNS) therapy for the treatment of TRD. METHODS: In a multicenter, double blind study, 331 patients with TRD were randomized to one of three dose groups: LOW (0.25 mA current, 130 µs pulse width), MEDIUM (0.5-1.0 mA, 250 µs), or HIGH (1.25-1.5 mA, 250 µs). A highly treatment-resistant population (>97% had failed to respond to ≥6 previous treatments) was enrolled. Response and adverse effects were assessed for 22 weeks (end of acute phase), after which output current could be increased, if clinically warranted. Assessments then continued until Week 50 (end of long-term phase). RESULTS: VNS therapy was well tolerated. During the acute phase, all groups showed statistically significant improvement on the primary efficacy endpoint (change in Inventory of Depressive Symptomatology-Clinician Administered Version [IDS-C]), but not for any between-treatment group comparisons. In the long-term phase, mean change in IDS-C scores showed continued improvement. Post-hoc analyses demonstrated a statistically significant correlation between total charge delivered per day and decreasing depressive symptoms; and analysis of acute phase responders demonstrated significantly greater durability of response at MEDIUM and HIGH doses than at the LOW dose. CONCLUSIONS: TRD patients who received adjunctive VNS showed significant improvement at study endpoint compared with baseline, and the effect was durable over 1 year. Higher electrical dose parameters were associated with response durability.

Use of standard Webcam and Internet equipment for telepsychiatry treatment of depression among underserved Hispanics.

OBJECTIVE: Depression affects nearly one in five Americans at some time in their life, causing individual suffering and financial cost. The Internet has made it possible to deliver telemedicine care economically to areas and populations with limited access to specialist or culturally and linguistically congruent care. METHODS: This study compared the effectiveness for Hispanic patients of depression treatment provided by a psychiatrist through Internet videoconferencing (Webcam intervention) and treatment as usual by a primary care provider. Adults (N=167) with a diagnosis of depression were recruited from a community clinic and were randomly assigned to treatment condition. Webcam participants met remotely each month with the psychiatrist, and treatment-as-usual patients received customary care from their primary care providers, all for six months. At baseline and three and six months, analyses of variance tested differences between conditions in scores on depression rating scales and quality-of-life and functional ability measures. RESULTS: All participants experienced an improvement in depression symptoms. Ratings on the Montgomery-Åsberg Depression Rating Scale by clinicians blind to treatment group and self-ratings on the nine-item Patient Health Questionnaire, Quality of Life Enjoyment and Satisfaction Questionnaire, and Sheehan Disability Scale showed a significant main effect of time. On all four measures, a significant interaction of time by intervention favoring the Webcam group was noted. DISCUSSION: Results suggest that telepsychiatry delivered through the Internet utilizing commercially available domestic Webcams and standard Internet and computer equipment is effective and acceptable. Use of this technology may help close the gap in access to culturally and linguistically congruent specialists.

Multifamily group psychoeducation and cognitive remediation for first-episode psychosis: a randomized controlled trial.

BACKGROUND: Multifamily group psychoeducation (MFG) has been shown to reduce relapse rates among individuals with first-episode psychosis. However, given the cognitive demands associated with participating in this intervention (e.g., learning and applying a structured problem-solving activity), the cognitive deficits that accompany psychotic disorders may limit the ability of certain individuals to benefit from this intervention. Thus, the goal of this study is to examine whether individuals with first-episode psychosis who participate simultaneously in MFG and cognitive remediation--an intervention shown to improve cognitive functioning among individuals with psychotic disorders--will be less likely to experience a relapse than individuals who participate in MFG alone. METHODS/DESIGN: Forty individuals with first-episode psychosis and their caregiving relative will be recruited to participate in this study. Individuals with first-episode psychosis will be randomized to one of two conditions: (i) MFG with concurrent participation in cognitive remediation or (ii) MFG alone. The primary outcome for this study is relapse of psychotic symptoms. We will also examine secondary outcomes among both individuals with first-episode psychosis (i.e., social and vocational functioning, health-related quality of life, service utilization, independent living status, and cognitive functioning) and their caregiving relatives (i.e., caregiver burden, anxiety, and depression) DISCUSSION: Cognitive remediation offers the possibility of ameliorating a specific deficit (i.e., deficits in cognitive functioning) that often accompanies psychotic symptoms and may restrict the magnitude of the clinical benefits derived from MFG. TRIAL REGISTRATION: ClinicalTrials (NCT): NCT01196286.

Symptoms of depression in a Hispanic primary care population with and without chronic medical illnesses.

OBJECTIVE: To describe somatic and psychiatric symptoms reported by Hispanic primary care patients with and without depression and/or chronic medical illnesses. METHOD: Adult Hispanic patients (n = 104) in a Mobile Health Program in underserved southern Arizona participated in a survey conducted between September 2006 and February 2007 to obtain information about the somatic and psychiatric symptoms that they were experiencing. They were asked to rate the severity of their symptoms listed in the depression screen Personal Health Questionnaire-9 (PHQ-9), the Symptom Checklist-90-Revised (SCL-90-R), and 5 new symptoms described by patients in focus groups conducted in the first phase of the project. Patients were categorized as depressed if their PHQ-9 scores were 10 or above, and they were further categorized as having or not having chronic illnesses based on self-report. Analyses of variance were conducted for each SCL-90-R symptom dimension to compare across the 4 groups (group 1: not depressed and not medically ill; group 2: medically ill but not depressed; group 3: depressed but not medically ill; and group 4: depressed and medically ill). RESULTS: Patients with chronic medical illnesses comorbid with depression were found to report significantly more somatic symptoms than those with only chronic medical illnesses or depression alone (P ≤ .001). They also reported significantly more psychopathology than patients with depression alone (P ≤ .05 or better). CONCLUSIONS: Patients with medical illnesses comorbid with depression are more likely to exhibit psychopathology than patients with medical illnesses or depression alone.

CSF neurochemicals during tryptophan depletion in individuals with remitted depression and healthy controls.

The purpose of this study was to examine the differential effects of acute tryptophan (TRP) depletion vs. sham condition on plasma, cerebrospinal fluid (CSF) biochemical parameters, and mood in the following three subject groups: (1) nine antidepressant-free individuals with remitted depression, (2) eight paroxetine-treated individuals with recently remitted depression, and (3) seven healthy controls. Plasma TRP decreased during TRP depletion and increased during sham condition (p<.01). CSF TRP and 5-hydroxyindoleacetic acid were lower during TRP depletion than sham condition (p<.01 each). During TRP depletion, CSF TRP correlated significantly with the plasma sum of large neutral amino acids (SigmaLNAA) (R=-.52, p=.01), but did not significantly correlate with plasma TRP (R=.15, p=.52). The correlation between CSF TRP and ratio of TRP to SigmaLNAA was R=.41 and p=.06 during TRP depletion, and R=-.44 and p=.04 during sham condition. A negative correlation trend was observed between CSF-TRP levels and peak Hamilton Depression Rating Scale scores during TRP depletion in patients recovered from depression (R=-.45, p=.07), but not in healthy controls (R=-.01, p=.98). CSF neuropeptide Y was higher during TRP depletion than sham condition (t=1.75, p<.10). These results illustrate the importance of assessing plasma SigmaLNAA when using the TRP depletion paradigm. The use of a single CSF sampling technique although practical may result in data acquisition limitations.

Polymorphisms of the HTR1a allele are linked to frontal brain electrical asymmetry.

Polymorphic variations in genes related to serotonin synthesis, transport, recognition, or degradation may convey subtle changes in serotonin system architecture that may place an individual at risk for psychopathology when faced with life stressors. The relationship between three key serotonin alleles and frontal brain electrical asymmetry, a putative endophenotype of depression, was examined. Risk alleles were hypothesized to predict relatively greater right frontal brain activity regardless of current clinical state. A sample of 313 college-age individuals, spanning a range of depressive severity from no symptomotology to clinically meaningful levels, participated. Resting encephalographic (EEG) activity was recorded from 64 scalp sites on four occasions separated by at least 24h (two 8-min recording sessions occurring at each occasion). Alpha power asymmetry scores between homologous sites were calculated for each session and then averaged to form a trait metric of asymmetry for each pair. PCR based genotyping was conducted for the HTR1a, HTR2a, and HTTLPR genes. Variations in the HTR1a gene were related to trait EEG asymmetry, regardless of any history of depression. Compared to subjects with at least one non-risk allele, subjects with homozygous HTR1A risk alleles had significantly greater relative right frontal activity at sites F7/F8, F5/F6, and F1/F2. In conclusion, variation in HTR1a can influence trait level brain activity, which may ultimately be indicative of risk for psychopathology.

Alteration of frontal EEG asymmetry during tryptophan depletion predicts future depression.

BACKGROUND: Tryptophan depletion (TD) reduces brain serotonin and may induce acute depressive symptomatology, especially among those with a history of Major Depression. Depressive response to TD among euthymic patients with a history of depression also predicts future depression. Better prediction might result by assessing a putative endophenotype for depressive risk, frontal electroencephalographic (EEG) asymmetry, in the context of TD. METHOD: Nine euthymic history-positive participants and nine controls were administered TD. Symptomatic and EEG frontal asymmetry data were collected for 6 h following TD, and clinical status was followed for the next 12 months. RESULTS: The magnitude of TD-induced change in frontal EEG asymmetry significantly predicted the development of depression during the ensuing six to twelve months, and with greater sensitivity than symptomatic response. LIMITATIONS: The results are tempered by the small sample size. CONCLUSIONS: Despite the limited sample size, these preliminary results suggest that TD-induced changes in frontal EEG asymmetry may provide a more sensitive indicator of risk for imminent depression than symptomatic response to TD.

Sex differences in depressive response during monoamine depletions in remitted depressive subjects.

OBJECTIVE: Although sex differences in the prevalence of depression are well known, the effects of sex on the underlying mechanisms of illness and on antidepressant action remain less clear. Tryptophan depletion and catecholamine depletion (via alpha-methylparatyrosine [AMPT] administration) are broadly utilized methods for studying the effects of the safe and transient reduction of serotonin and catecholamine neuro-transmission, respectively. The present study assessed the effects of sex on the mood response during acute monoamine depletion. METHOD: Data on Hamilton Rating Scale for Depression (HAM-D) scores during depletion tests were analyzed retrospectively in 59 subjects (41 women, 18 men) who underwent tryptophan depletion and 39 subjects (25 women, 14 men) who underwent catecholamine depletion. All subjects were in remission from a DSM-IV-defined major depressive episode. Data reviewed included subjects enrolled between November 1993 and November 1997. RESULTS: Significant increases in HAM-D scores were observed in response to both depletion procedures, with a similar magnitude of change. Analysis of variance with repeated measures of HAM-D scores revealed a significant main effect of time for tryptophan depletion (F = 7.31, df = 3, p < .01) and for catecholamine depletion (F = 9.61, df = 4, p < .01). Time-by-sex interaction was significant for tryptophan depletion (F = 4.04, df = 3, p = .01), but not for catecholamine depletion (F = 0.75, df = 4, p = .57). Depressive symptoms were significantly greater in women during tryptophan depletion (t test p < .01), while no significant sex differences were found during catecholamine depletion. CONCLUSIONS: These findings suggest that the effect of sex in depressive vulnerability may be related to differential sex effects in monoaminergic function.

Number of risk genotypes is a risk factor for major depressive disorder: a case control study.

BACKGROUND: The objective of the study was to determine the genetic basis of Major Depressive Disorder, and the capacity to respond to antidepressant treatment. An association study of 21 candidate polymorphisms relevant to monoamine function and the mechanism of antidepressant response was conducted in 3 phenotypically distinct samples: a group with chronic or recurrent depression unable to respond to antidepressants (non-responders) (n = 58), a group capable of symptomatic improvement with or without treatment (responders) (n = 39), and volunteer controls (n = 85). The responders and non-responders constituted a larger group of depressed subjects. METHODS: A candidate gene approach was employed to asses the genetics basis of Major Depressive Disorder. The genotypic frequencies of selected polymorphisms were compared between the controls and depressed subjects. To asses the genetics basis of the capacity to respond to antidepressant treatment, the responders were compared to the non-responders. Candidate genes were chosen based on functional studies and proximity to whole genome linkage findings in the literature. Risk genotypes were identified by previous functional studies and association studies. RESULTS: A statistically significant difference in genotype frequency for the SLC6A4 intron 2 VNTR was detected between the subjects with a history of depression and controls (p = 0.004). Surprisingly, a statistically significant difference was detected between responders and non-responders for the DRD4 exon III VNTR genotype frequencies (p = 0.009). Furthermore, a difference between the controls and depressed subjects as well as between the controls and non-responders was detected for the number and distribution of risk genotypes in each group. CONCLUSION: An association between several monoamine-related genes and Major Depressive Disorder is supported. The data suggest that the two depressive phenotypes are genetically different, inferring that the genetic basis for the capacity to respond to standard antidepressant treatment, and the genetic susceptibility to Major Depressive Disorder may be independent. In addition, a proof of concept is provided demonstrating that the number of risk genotypes may be an indication of susceptibility of major depressive disorder and the severity of the disorder.

Acupuncture for depression: a randomized controlled trial.

OBJECTIVE: To assess the efficacy of acupuncture as an intervention for major depressive disorder (MDD). METHOD: Acupuncture was examined in 151 patients with MDD (DSM-IV) who were randomly assigned to 1 of 3 groups in a double-blind randomized controlled trial. The specific intervention involved Traditional Chinese Medicine (TCM)-style acupuncture with manual stimulation for depression; the control conditions consisted of (1) a nonspecific intervention using a comparable number of legitimate acupuncture points not specifically targeted to depressive symptoms and (2) a waitlist condition, which involved waiting without intervention for 8 weeks. After 8 weeks, all patients received the depression-specific acupuncture. Each 8-week intervention regimen consisted of 12 acupuncture sessions delivered in an acupuncturist's office in the community. The primary outcome measure was the 17-item Hamilton Rating Scale for Depression. The study was conducted from February 1998 to April 2002. RESULTS: Twenty patients terminated treatment before the completion of the 8-week intervention (13%) but not differentially by study group. Random regression models of the intent-to-treat sample revealed that although patients receiving acupuncture improved more than those awaiting intervention, no evidence of differential efficacy of the depression-specific over nonspecific intervention was found. Response rates in acupuncture-treated patients were relatively low after 8 weeks (22% and 39% for specific and nonspecific intervention groups, respectively), with the response rate after the entire 16-week trial reaching 50%. CONCLUSION: Although TCM manual acupuncture is a well-tolerated intervention, results fail to support its efficacy as a monotherapy for MDD. It can't be ruled out that factors unique to the implementation of acupuncture in this research study may have limited the efficacy of interventions compared to those provided in naturalistic settings. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov identifier NCT00010517.

Safety, tolerability, and efficacy of psilocybin in 9 patients with obsessive-compulsive disorder.

BACKGROUND: Anecdotal reports suggest that psychedelic agents may relieve symptoms of obsessive-compulsive disorder (OCD). This modified double-blind study investigated the safety, tolerability, and clinical effects of psilocybin, a potent 5-HT(1A) and 5-HT(2A/2C) agonist, in patients with OCD. METHOD: Nine subjects with DSM-IV-defined OCD and no other current major psychiatric disorder participated in up to 4 single-dose exposures to psilocybin in doses ranging from sub-hallucinogenic to frankly hallucinogenic. Low (100 microg/kg), medium (200 microg/kg), and high (300 microg/kg) doses were assigned in that order, and a very low dose (25 microg/kg) was inserted randomly and in double-blind fashion at any time after the first dose. Testing days were separated by at least 1 week. Each session was conducted over an 8-hour period in a controlled environment in an outpatient clinic; subjects were then transferred to a psychiatric inpatient unit for overnight observation. The Yale-Brown Obsessive Compulsive Scale (YBOCS) and a visual analog scale measuring overall obsessive-compulsive symptom severity were administered at 0, 4, 8, and 24 hours post-ingestion. The Hallucinogen Rating Scale was administered at 8 hours, and vital signs were recorded at 0, 1, 4, 8, and 24 hours after ingestion. The study was conducted from November 2001 to November 2004. RESULTS: Nine subjects were administered a total of 29 psilocybin doses. One subject experienced transient hypertension without relation to anxiety or somatic symptoms, but no other significant adverse effects were observed. Marked decreases in OCD symptoms of variable degrees were observed in all subjects during 1 or more of the testing sessions (23%-100% decrease in YBOCS score). Repeated-measures analysis of variance for all YBOCS values revealed a significant main effect of time on Wilks lambda (F = 9.86, df = 3,3; p = .046), but no significant effect of dose (F = 2.25, df = 3,3; p = .261) or interaction of time and dose (F = 0.923, df = 9,45; p = .515). Improvement generally lasted past the 24-hour timepoint. CONCLUSIONS: In a controlled clinical environment, psilocybin was safely used in subjects with OCD and was associated with acute reductions in core OCD symptoms in several subjects.

Carnitine levels in valproic acid-treated psychiatric patients: a cross-sectional study.

BACKGROUND: Carnitine facilitates the transport of long-chain fatty acids across the mitochondria for beta oxidation, and the removal of potentially toxic acylcoenzyme-A metabolites from the inner aspect of mitochondrion as acylcarnitines. Previous studies suggest a significant decrease in carnitine concentrations and changes in the ratio of acylcarnitine to free carnitine in seizure-disoriented patients treated with valproic acid (VPA), which may lead to clinical manifestations of carnitine deficiency. This study sought to explore whether the same decrease in plasma free carnitine and increase in acylcarnitines are seen when VPA is used in the treatment of patients with psychiatric disease. METHOD: Thirty psychiatric patients treated with VPA for at least six months were selected for the study and granted informed consent for participation. Exclusion criteria included liver disorder or pancreatitis, metabolic defects known to affect plasma carnitine levels, or noncompliance with VPA regimen. Plasma free carnitine, total carnitine, VPA, and amylase levels were determined, and liver function tests (LFTs) were performed. Pearson correlations were conducted between VPA levels, levels and ratios of carnitines, as well as LFTs and amylase levels. RESULTS: Plasma free and total carnitine levels were lower than the reported normal range for the laboratory performing the assay, and the ratio of acylcarnitine to free carnitine was increased. There was a significant positive correlation of VPA levels and acylcarnitine-free carnitine ratio, a trend toward significance between VPA levels and acylcarnitine levels, and a marginal negative correlation between VPA levels and free carnitine levels. VPA levels correlated also with several LFTs and acylcarnitine levels. Octanoyl carnitine and acylcarnitine levels, as well as acylcarnitine-free carnitine and octanoyl-free carnitine ratios, correlated significantly with amylase levels. CONCLUSION: Although the study was limited by a cross-sectional design without direct control comparison, the findings suggest that patients with various psychiatric conditions treated with polypharmacy that includes VPA may have lower plasma carnitine levels than would be expected in healthy controls.