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 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
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
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
Mathieu Fradet, Cecelia Kelly, Anna J. Donnelly et al.
No Summary
CNS Spectrums
January 1, 2025
Emma O’leary, Seetal Dodd, Stephen 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
April 1, 2023
Amanda Jones, Caroline Streicher, Shawn Alter et al.
In patients with major depressive disorder who had not improved after one prior antidepressant in the current episode, treatment with AXS-05 (dextromethorphan HBr 45 mg-bupropion HCl 105 mg) led to rapid and sustained improvements in depression and functioning. Mean scores on the Montgomery-Åsberg Depression Rating Scale (MADRS) dropped by 9.1 points at one week, 13.3 points at two weeks, and 20.4 points at six weeks. Remission (MADRS score of 10 or less) was achieved by 5.7% of patients at one week, 16.2% at two weeks, and 46.0% at six weeks. Improvements in functioning were seen starting at one week and were maintained at 12 months. Common side effects included COVID-19 infection, nausea, headache, dry mouth, insomnia, and dizziness.
CNS Spectrums
April 1, 2023
Amanda Jones, Caroline Streicher, Shawn Alter et al.
AXS-05 (dextromethorphan-bupropion) is an oral NMDA receptor antagonist being developed for major depressive disorder. In two double-blind, randomized, controlled 6-week trials, AXS-05 showed rapid antidepressant effects. In the placebo-controlled GEMINI trial (327 participants), AXS-05 was superior to placebo on depressive symptom improvement starting at Week 1, with greater improvement on the MADRS scale (7.3 vs. 4.9 points), higher response rates (15% vs. 7%), and by Week 2, higher remission rates (17% vs. 8%). In the ASCEND trial (80 participants) comparing AXS-05 to bupropion alone, AXS-05 was superior from Week 2 on MADRS improvement (12.5 vs. 7.8 points) and remission (26% vs. 3%). Common adverse events included dizziness, nausea, headache, diarrhea, somnolence, and dry mouth.
CNS Spectrums
April 1, 2023
Amanda Jones, Roger S. McIntyre, Mark Jacobsen et al.
AXS-05 (dextromethorphan-bupropion) rapidly and significantly reduced anhedonic symptoms in adults with major depressive disorder. In a 6-week randomized, double-blind, placebo-controlled trial with 327 participants, those receiving AXS-05 showed a mean reduction of 4.44 points on the MADRS anhedonia subscale at Week 1 versus 2.69 points for placebo, and a reduction of 9.70 points at Week 6 versus 7.22 for placebo. Response rates were significantly greater for AXS-05 from Week 1 onward. Common adverse events included dizziness, nausea, and headache.
CNS Spectrums
September 30, 2019
S. Stahl
Standard antidepressants boost monoamine levels quickly, but therapeutic effects often take weeks and many patients with major depressive disorder do not respond adequately to first- or second-line monoamine-targeting treatments. The recent approval of the NMDA antagonist esketamine (intranasal) for treatment-resistant depression highlights the need for rapid-acting drugs with different mechanisms. Dextromethorphan/bupropion, an investigational medicine in development, is one such candidate.