CNS Spectrums
June 25, 2020
Giovanni Martinotti, Luisa de Risio, Chiara Vannini et al.
102 citations
About 25% of first-episode psychoses are substance-induced. The DSM-5 definition assumes symptoms are transient and disappear after sustained abstinence, but this does not account for persistent cases. A new diagnostic framework is needed to differentiate comorbid conditions from substance-related psychoses. The authors propose a novel clinical entity called substance-related exogenous psychosis (SREP), covering both transient and persistent psychoses linked to substance use. SREP is distinct from schizophrenia, characterized by altered consciousness, persecutory delusions, visual and cenesthetic hallucinations, impulsivity, psychomotor agitation, affective and negative symptoms, a pervasive feeling of unreality, and intact insight. Delusions are secondary to abnormal perception from a 'sensorialization' of the world. Longitudinal studies are needed to validate this category.
CNS Spectrums
September 30, 2021
Xénia Gonda, Péter Döme, Joanna C. Neill et al.
77 citations
Major depressive disorder (MDD) and treatment-resistant depression (TRD) remain inadequately addressed by current antidepressants, which have limited efficacy or undesirable side effects linked to their actions on monoamine neurotransmitters (serotonin, norepinephrine, dopamine). New drugs targeting non-monoamine pathways, such as the recently approved intranasal Esketamine (a glutamatergic agent) combined with an oral antidepressant for adult TRD, offer promise. Several glutamatergic and GABAergic drugs are in clinical development, and preliminary positive trial results with psychedelics like psilocybin, Ayahuasca, 5-MeO-DMT, and LSD suggest they may become effective therapies. Expanding beyond monoamine targets appears to yield antidepressants with superior efficacy, safety, and tolerability.
CNS Spectrums
July 11, 2022
Seetal Dodd, Trevor R. Norman, Harris A. Eyre et al.
61 citations
Psilocybin, a tryptamine alkaloid found in Psilocybe mushrooms, is metabolized into the active compound psilocin, which produces psychoactive effects primarily by partially activating the 5HT2A receptor. Psilocin also binds to other receptor subtypes, though these actions are not fully understood. Clinical trials have tested psilocybin at hallucinogenic doses for addictive disorders, anxiety, and depression. This review assesses psilocybin and psilocin as potential neuropsychiatric treatments, weighing therapeutic benefits against potential harms. The authors conclude that careful evaluation of the number needed to harm versus the number needed to treat will determine clinical viability, and they call for a responsible path forward in this field.
CNS Spectrums
June 19, 2019
Gregor Hasler
31 citations
Around 50% of people with major depression respond to monoaminergic antidepressants, which modulate synapses but do not substantially influence synaptogenesis. They also increase brain-derived neurotrophic factor (BDNF), but for activity-dependent plasticity, BDNF release must work with synaptogenesis. Ketamine, in contrast, leads to fast changes in synaptic function and plasticity beyond classical antidepressants, suggesting it could enhance psychotherapy effects. Since ketamine's purely pharmacological effect is transient, such enhancement may become an important clinical indication. The editorial outlines mechanistic hypotheses for how Behavioral Activation, Trauma-Focused Psychotherapies, and Humanistic Psychotherapy may prolong ketamine's antidepressant effects.
CNS Spectrums
December 3, 2020
Orly Lipsitz, Roger S McIntyre, Nelson B Rodrigues et al.
25 citations
Higher body mass index (BMI) does not predict how well patients with treatment-resistant depression respond to intravenous (IV) ketamine. In a study of 230 adults who received four ketamine infusions, people with normal weight, overweight, and obesity (classes I and II) showed similar improvements in depression, suicidal thoughts, anxiety, anhedonia, and daily functioning. The antidepressant effects and rates of partial response, response, and remission were comparable across all BMI groups. The findings are limited by the observational, open-label design of this retrospective analysis.
CNS Spectrums
December 10, 2020
Nelson B Rodrigues, Ashley N. Siegel, Orly Lipsitz et al.
17 citations
Intravenous (IV) ketamine effectively reduces symptoms of depression, suicidal ideation, anxiety, and anhedonia in adults with treatment-resistant depression, regardless of whether they have previously undergone neurostimulation. In a retrospective analysis of 238 patients, those without prior neurostimulation experienced an average 6.4-point reduction on a depression severity scale, while those with a history of neurostimulation showed a 4.3-point reduction. No significant differences emerged between the groups, indicating that IV ketamine benefits even highly intractable patients.
CNS Spectrums
November 20, 2024
Rafael Guimarães Dos Santos, Jaime Eduardo Cecilio Hallak
13 citations
Ayahuasca, a botanical hallucinogen traditionally used by indigenous groups in Northwestern Amazonia, is prepared from plants containing DMT and harmine. Interest in its therapeutic potential for psychiatric disorders is growing. Human studies suggest good safety and tolerability, often with improvements in depressive and anxious symptoms. However, controlled studies are few, involve small samples, single doses, and short follow-ups. Larger trials with varied doses are needed to evaluate potential benefits.
CNS Spectrums
December 1, 2024
Mathieu Fradet, Carlton M Kelly, Anna Donnelly et al.
10 citations
Psilocybin therapy shows promise as a new treatment for depression and other mental health disorders. The chapter reviews recent data on its safety and efficacy, describes how the therapy is delivered and its subjective effects, and outlines current understanding of psilocybin's pharmacology and neurobiological effects. Other psychedelic substances with therapeutic potential are also briefly discussed.
CNS Spectrums
October 31, 2024
Sabrina Wong, Gia Han Le, Angela T H Kwan et al.
10 citations
A systematic review and meta-analysis of seven randomized controlled trials found that a single dose of esketamine given around childbirth significantly reduced the incidence of postpartum depression (PPD). Within one week of delivery, the odds of a PPD diagnosis were 70% lower for those who received esketamine compared to a control; between four and six weeks postpartum, the odds were 67% lower. The results suggest that esketamine may have preventive antidepressant effects during the postpartum period, with implications for both the mechanisms and clinical treatment of PPD.
CNS Spectrums
January 17, 2025
Roger S McIntyre, Gregory W Mattingly, Yordan Godinov et al.
9 citations
In adults with treatment-resistant depression, esketamine nasal spray combined with an oral antidepressant leads to higher remission rates than quetiapine extended-release combined with an oral antidepressant. Starting at week 8, 28.3% of esketamine-treated patients achieved remission compared to 18.6% on quetiapine, and by week 32, 55.7% versus 36.3%. Depressive symptoms improved more with esketamine from day 8 onward. Fewer patients stopped treatment due to side effects with esketamine (4.5%) than with quetiapine (10.1%). These results come from a secondary analysis of a randomized trial.
CNS Spectrums
December 1, 2024
Mauro Scala, Chiara Fabbri, Paolo Fusar‐poli et al.
8 citations
Psilocybin shows promise for treating mood and anxiety disorders, obsessive-compulsive disorder, post-traumatic stress disorder, and substance use disorder, but significant evidence gaps remain. Current studies suggest psilocybin may alleviate depression, anxiety, obsessions, compulsions, and addictive behaviors, yet comparisons with standard antidepressants or anxiolytics are lacking, and optimal dosage, long-term efficacy, and safety are unclear due to trial limitations. Real-world implementation faces challenges including infrastructural requirements, personnel training, cultural stigma, and unresolved legal and ethical issues. Larger, more rigorous studies are needed to substantiate the evidence base before psilocybin can transition from research to clinical practice.
CNS Spectrums
June 30, 2025
Jose-Manuel Quintero, Rosa-Helena Bustos, Sharon Lechtig-Wassermann et al.
6 citations
Ketamine, first made in 1962, has become important for its fast-acting and lasting antidepressant effects in people with treatment-resistant depression. Unlike older antidepressants, it works through multiple brain chemical systems, including blocking NMDA receptors and boosting AMPA receptors. It also remains a useful anesthetic and painkiller for acute and chronic pain, and shows anti-inflammatory, neuroprotective, and possible antitumor properties. However, its dissociative and hallucinogenic effects lead to recreational misuse, which can cause bladder and liver problems. Its rediscovery as an antidepressant in the early 2000s transformed psychiatric care, and research now explores its use in bipolar depression, PTSD, OCD, and substance use disorders. The review covers ketamine's many uses and the need to balance benefits with risks.
CNS Spectrums
July 29, 2022
Ibrahim Turkoz, Oliver Lopena, Giacomo Salvadore et al.
6 citations
In adults with major depressive disorder and active suicidal ideation with intent who did not show early improvement, adding esketamine nasal spray to standard care increased the likelihood of achieving a response (63.9% vs 48.0%) and remission (35.1% vs 24.4%) after four weeks compared to placebo plus standard care. The odds of response were nearly double with esketamine. Similar benefits appeared for those who had not responded after one week. The findings suggest that continuing esketamine treatment for the full four weeks can be beneficial even when early response is absent.
CNS Spectrums
January 30, 2025
Steve O'Brien, David Nutt
5 citations
MDMA-assisted therapy (MDMA-AT) for PTSD and other behavioral disorders has a controversial history, moving from research to recreational use and back to medicine. Pivotal trials have been conducted, but recent setbacks have hindered clinical application. The chapter argues that MDMA-AT still holds potential to transform psychiatry, though its future is uncertain due to ongoing debates over ethics, methodology, and political influence.
CNS Spectrums
November 21, 2024
Elena Koning, Elvina M Chu, Elisa Brietzke
5 citations
Psychedelics alter consciousness and have been used for centuries by indigenous communities, but only recently studied as therapeutic tools in psychotherapy. Since the early twentieth century, psychedelic-assisted psychotherapy has been explored for neuropsychiatric conditions with rigid thought patterns and treatment resistance. This emerging field has faced opposition from mid-twentieth century counterculture associations, media sensationalism, legislative restrictions, and scientific criticisms like 'breaking the blind' and 'excessive enthusiasm.' This perspective article examines that historical opposition and its implications for the field's credibility. Drawing lessons from history can aid clinical research in psychiatry amid drug policy reform.
CNS Spectrums
June 1, 2024
Jennifer Kern Sliwa, Ronaldo R Naranjo, Ibrahim Turkoz et al.
5 citations
In adults with treatment-resistant depression, adding esketamine nasal spray to a newly initiated oral antidepressant led to greater improvement in depressive symptoms than oral antidepressant plus placebo spray. Across two short-term trials, the group receiving esketamine plus oral antidepressant showed a mean reduction of 12.8 points on the Patient Health Questionnaire-9 (PHQ-9) at 28 days, compared with 10.3 points in the placebo group, a statistically significant difference. 77.1% of patients in the esketamine group achieved a clinically meaningful improvement (at least a 6-point drop) versus 64% in the placebo group. In a separate relapse-prevention study, 57.3% of patients on esketamine plus oral antidepressant maintained remission (PHQ-9 score ≤4) versus 44.2% on oral antidepressant plus placebo. The self-reported PHQ-9 results aligned with clinician-rated Montgomery-Åsberg Depression Rating Scale scores.
CNS Spectrums
November 20, 2024
Angela T H Kwan, Moiz Lakhani, Gurkaran Singh et al.
4 citations
Ketamine shows potential for treating PTSD, OCD, and alcohol use disorders beyond its established use for depression. A systematic review and meta-analysis of 44 studies found that ketamine significantly reduced PTSD symptoms measured by the PCL-5 (average decrease of 28 points) and CAPS-5 (average decrease of 14 points), and OCD symptoms measured by the Y-BOCS (average decrease of 8 points). For alcohol use disorders, ketamine treatment was associated with reduced urge to drink, higher abstinence rates, and longer time to relapse. However, the small number of randomized controlled trials highlights the need for more research on ketamine's short- and long-term benefits and risks for these conditions.
CNS Spectrums
August 12, 2025
Gia Han Le, Sabrina Wong, Stavroula Bargiota et al.
3 citations
G protein-coupled receptors (GPCRs) are involved in many bodily processes. Traditional drug classification divides ligands into agonists or antagonists. Biased agonism is a newer concept where a drug selectively activates one intracellular signaling pathway over another, such as G protein versus β-arrestin pathways. This narrative review of literature up to April 2025 describes distinct mechanisms of antagonism and agonism beyond conventional models. Biased agonism has shown potential for greater efficacy, as with the incretin receptor agonist tirzepatide, and improved safety, as with certain serotonergic psychedelics and opioids. Preclinical evidence suggests biased agonism could improve psychiatric and neurological treatments by differentially activating pathways, pending clinical validation.
CNS Spectrums
December 12, 2024
Alberto Carrara
2 citations
A neuroethical framework integrates neuroscience and philosophy to examine how different levels of consciousness—from interoception to self-awareness—shape free will and autonomy, especially in psychiatric and neurological disorders. The analysis proposes a multidimensional, bottom-up approach linking neurobiological processes to distinct types of freedom, such as 'intero-freedom' tied to internal bodily states and 'self-freedom' linked to higher self-awareness. This stratification shows how neurological conditions can impair patients' freedom of choice, raising ethical concerns. The framework aims to guide more tailored treatments that restore autonomy and respect dignity, advocating for healthcare policies that enhance personal freedom for those with mental health challenges.
CNS Spectrums
April 1, 2021
Steve Best, Dan G. Pavel, Natalie Haustrup
1 citation
Combining repetitive transcranial magnetic stimulation (rTMS) with intravenous ketamine infusions—called combination TMS with ketamine (CTK)—produced substantial and lasting reductions in depressive symptoms for 28 adults with treatment-resistant depression. Patients received three CTK sessions per week, with rTMS applied to the mid-prefrontal area and ketamine doses adjusted by biomarker levels. Symptom severity, measured by the Clinical Global Impression scale, dropped significantly after treatment, and the improvement persisted for at least two years. The findings suggest CTK may help patients who have not responded to other treatments, but randomized controlled trials are needed to confirm the results.
CNS Spectrums
March 10, 2026
Halima Faisal, Gia Han Le, Angela T H Kwan et al.
Ketamine rapidly alters brain reward circuitry in people with major depressive disorder, particularly in fronto-striatal and limbic networks. In a synthesis of 13 neuroimaging studies involving 623 participants (482 with depression, 141 controls), intravenous ketamine (typically 0.5 mg/kg over 40 minutes) changed resting-state connectivity in ventral striatal-prefrontal and default mode, salience, and executive networks within 2 to 48 hours, with some effects lasting up to 10 days. Task-based imaging showed altered ventral striatal responses during reward anticipation and feedback, and changes in medial prefrontal activity during emotion processing. PET scans indicated increased prefrontal-cingulate metabolism and region-specific serotonin receptor binding changes. Few studies directly measured anhedonia, suggesting the findings reflect broader antidepressant mechanisms.
CNS Spectrums
January 1, 2025
Emma O’leary, Seetal Dodd, Stephen M Stahl
Psychoactive substances like psychedelics, cannabis, and stimulants are being reconsidered for therapeutic use, but their histories in non-medical contexts raise ethical and regulatory challenges. This review examines the ethical issues shaping research and prescribing, highlighting diverse perspectives from Indigenous, philosophical, psychiatric, and user communities. Key concerns include balancing therapeutic benefits against misuse risks, ensuring rigorous science, and addressing sociopolitical factors that influence public perception and policy. The article calls for evidence-based frameworks that prioritize patient safety and recognize social and commercial determinants of health, extending ethics beyond prescribing. It critically assesses the promise and limitations of repurposing these substances for contemporary psychiatric practice.
CNS Spectrums
January 1, 2025
Mathieu Fradet, Cecelia Kelly, Anna Donnelly et al.
No Summary
CNS Spectrums
April 1, 2020
Leslie Citrome, Allitia DiBernardo, Jaskaran Singh
In people with treatment-resistant depression, adding esketamine nasal spray to an oral antidepressant is more effective than an antidepressant plus placebo for both acute and long-term treatment. For every 8 patients treated, one additional patient achieves a 50% or greater reduction in depressive symptoms; for every 6 patients, one additional patient achieves remission. Common side effects include dissociation, vertigo, nausea, dizziness, and dysgeusia, each occurring in roughly 1 in 5 to 1 in 4 patients. Discontinuation due to side effects is uncommon. Patients are about 3 times more likely to achieve remission than to stop treatment due to a side effect.
CNS Spectrums
February 1, 2018
Abigail I. Nash, M. Shawi, Jaskaran Singh et al.
In a post-hoc analysis of a Phase 2a clinical trial, adults with treatment-resistant major depressive disorder who had not responded to at least two prior antidepressants received twice-weekly intranasal esketamine (28 mg, 56 mg, or 84 mg) or placebo for one week. At all doses, patients reported a one-point average improvement on the Patient Global Impression Severity scale, while placebo patients reported no change. Clinician ratings on the Clinical Global Impression Severity scale similarly improved for esketamine groups but not for placebo. These results suggest that esketamine can produce clinically meaningful improvement in depression symptoms within one week, as reported by both clinicians and patients, consistent with prior findings using the Montgomery-Åsberg Depression Rating Scale.