World Psychiatry
September 15, 2023
Roger S. McIntyre, Mohammad Alsuwaidan, Bernhard T. Baune et al.
712 citations
At least 30% of people with depression meet the common definition of treatment-resistant depression (TRD): inadequate response to two or more antidepressants despite adequate trials and adherence. Many cases are actually pseudo-resistant due to insufficient treatment or non-adherence. No consensus definition with proven predictive utility for clinical decisions exists, leading to varied prevalence estimates and inconsistent care. Intravenous ketamine and intranasal esketamine are effective for TRD. Some second-generation antipsychotics (e.g., aripiprazole, quetiapine XR) help as adjuncts in partial responders, but only the olanzapine-fluoxetine combination has been studied in FDA-defined TRD. Repetitive transcranial magnetic stimulation and electroconvulsive therapy are established effective interventions. Evidence for extending trials, switching, or combining antidepressants is mixed, and manual-based psychotherapies are not effective alone but help when added to antidepressants.
World Psychiatry
February 1, 2016
Fabrizio Schifano, Laura Orsolini, G. Duccio Papanti et al.
319 citations
Novel psychoactive substances encompass a wide variety of drugs, including synthetic cannabinoids, cathinone derivatives, psychedelic phenethylamines, novel stimulants, synthetic opioids, tryptamine derivatives, dissociatives, piperazines, GABA receptor agonists, prescribed medications, psychoactive plants, and performance-enhancing drugs. Users are often drawn to them for intense psychoactive effects and their likely undetectability in routine drug tests. These substances act on neurotransmitter pathways such as dopamine, cannabinoid CB1, GABA-A/B, 5-HT2A, glutamate, and kappa opioid receptors—systems whose imbalance is linked to mental health conditions. The paper provides psychiatrists with updated knowledge on the clinical pharmacology and psychopathological consequences of these drugs, along with a brief overview of clinical management.
World Psychiatry
September 25, 2015
Carlos A. Zarate, Mark J. Niciu
63 citations
Ketamine, an NMDA receptor antagonist, produces rapid and robust antidepressant effects in patients with treatment-resistant major depressive disorder and bipolar depression. Sub-anesthetic dose infusions (0.5 mg/kg for 40 minutes) show efficacy within 24 hours, with relapse often within one week. Ketamine also rapidly reduces suicidal thinking. The drug's mechanism involves blocking NMDA receptors on inhibitory interneurons, leading to increased glutamate release and activation of AMPA receptors, which triggers intracellular signaling cascades that stimulate synaptic plasticity. Challenges include lack of FDA approval, need for standardized dosing and administration, and risks of abuse and long-term side effects with repeated use. Future research requires better control conditions, identification of enriched subgroups, and development of glutamate biomarkers.
World Psychiatry
September 7, 2018
Robin Carhart‐Harris
49 citations
Serotonin is a complex neuromodulator involved in brain development, perception, cognition, and mood, but no unified theory of its function exists, partly due to its 14+ receptors. While SSRIs are the dominant depression treatment, their widespread use has not reduced depression prevalence, and questions about safety and efficacy persist. Evidence suggests serotonergic processes mediate sensitivity to context, with genetic and pharmacological factors interacting with environment to affect mental health.
World Psychiatry
June 1, 2024
35 citations
Meditation and psychedelics both appear to alter self-referential processing, potentially leading to experiences of self-transcendence. This review examines whether scientific investigation of self-transcendence through these methods has clinical relevance. The authors suggest that changes in self-referential processing may underlie therapeutic benefits for mental health conditions, though the exact mechanisms remain unclear. The paper argues that understanding how meditation and psychedelics modulate the sense of self could inform new treatments for disorders characterized by maladaptive self-focus, such as depression and anxiety.
World Psychiatry
May 18, 2021
Wayne Hall
17 citations
Psychedelic drugs such as psilocybin, LSD, and MDMA produce profound changes in thought, mood, and perception by acting on the 5-HT2A serotonin receptor. Over the past two decades, clinical research has revived, with phase 2 trials showing substantial benefits of psilocybin for treatment-resistant depression and MDMA-assisted psychotherapy for PTSD. Psilocybin has a shorter duration of action (4–6 hours) than LSD and is less likely to cause adverse reactions. A single dose can produce immediate clinical response sustained for six months in many patients, unlike standard antidepressants. However, trials have been limited to small, selected samples due to philanthropic funding constraints. Major challenges include impossibility of blinding in placebo-controlled trials and risk of off-label use outpacing evidence. Independent, publicly funded trials with larger, representative samples and longer follow-up are needed.
World Psychiatry
January 14, 2023
Oliver Howes, Luke Baxter
16 citations
Between 2011 and 2021, the FDA approved only 12 new drugs in psychiatry, compared to 50 in neurology and 135 in oncology, highlighting a deadlock in psychiatric drug development. Challenges include high placebo response rates in clinical trials, which necessitate large, expensive, multi-site studies that may worsen the problem, and the withdrawal of major pharmaceutical companies from the field. Most drugs in development target existing mechanisms rather than novel ones. Potential solutions include using fewer, higher-quality trial sites, digital technologies for standardization, and smart trial designs. Attracting new companies requires sustained investment in translational research, government and charitable funding, pre-competitive partnerships, and incentives like tax breaks. Advancing understanding of neurobiology and developing biomarkers are essential for creating mechanistically distinct treatments.
World Psychiatry
January 12, 2024
Marc J. Weintraub, David J. Miklowitz
6 citations
Psychedelic-assisted therapy (PAT) combines preparation, drug administration, and integration, but its methods have remained largely unchanged since the 1950s. Preparation typically lasts two to eight hours over one to three sessions, while drug sessions involve 6-8 hours of monitored introspection with eyeshades and classical music. Integration varies widely, from a single phone call to nine psychotherapy sessions, often using non-directive approaches from psychoanalysis or person-centered therapy. The text argues that these psychosocial components have not been rigorously tested for their relative benefits and recommends updating them with evidence-based treatments like cognitive-behavioral therapy (CBT), which targets shared mechanisms of emotional regulation, cognitive flexibility, and prosocial engagement. Combining psychedelics with structured psychotherapy may produce synergistic, longer-lasting improvements.
World Psychiatry
June 1, 2026
In a US population-based study, about 1 in 20 people who used psychedelics reported experiencing sexual or physical violence during their use. Younger age, female gender, and use of certain psychedelics like MDMA were associated with higher risk. The findings suggest that while most psychedelic experiences are safe, a minority involve violence, highlighting the need for harm reduction strategies.
World Psychiatry
September 15, 2023
Guy M. Goodwin
Psilocybin, once metabolized to psilocin, activates 5-HT2A receptors, enhancing cortical GABA function and brain connectivity. The largest randomized controlled trial of psilocybin in treatment-resistant depression (COMP 001) showed a dose-effect relationship: 25 mg of COMP360 produced significantly greater reduction in depressive symptoms than 1 mg at 3 weeks, with 10 mg intermediate. The psychedelic experience is variable, making unblinding unlikely to explain results. Psychological support—preparation, minimal guidance during the session, and integration—differs from psychotherapy, and mood improvement was evident the day after drug administration, before integration. The author argues psilocybin's antidepressant effect is primarily drug-driven, not psychotherapeutic.