Journal of Psychiatric Research
May 1, 2022
Yazen Alnefeesi, D. Chen-Li, Ella Krane et al.
177 citations
Ketamine shows substantial real-world antidepressant effects in treatment-resistant depression, with about 45% of patients responding and 30% achieving remission, based on a systematic review and meta-analysis of 79 studies involving 2665 patients. The effect varies considerably among individuals; more treatment-resistant cases remit less often, but response rates do not differ. The therapeutic benefit does not significantly decline with repeated treatments, indicating that even the most treatment-resistant patients may benefit and that mid-to-long term treatment is effective for many.
Journal of Psychiatric Research
December 11, 2020
Jiaqi Xiong, Orly Lipsitz, D. Chen-Li et al.
122 citations
A meta-analysis of nine randomized controlled trials (197 participants) found that a single dose of intravenous ketamine or intranasal esketamine is associated with large reductions in suicidal thoughts at 2, 4, and 24 hours after administration. The pooled effect size for intravenous racemic ketamine at 24 hours was 1.035, and for intranasal esketamine it was 1.309. No trials of intramuscular, oral, or sublingual ketamine reported anti-suicidal ideation effects suitable for quantitative analysis. The authors suggest that further studies are needed to evaluate these other routes of delivery and to compare formulations.
Journal of Psychiatric Research
July 1, 2021
Ashley N. Siegel, Shakila Meshkat, Katie Benitah et al.
101 citations
A review of clinical trials registered on clinicaltrials.gov as of December 3, 2020, shows that 70 studies are evaluating psychedelics (excluding ketamine) for psychiatric disorders. Most studies focus on MDMA (45.7%) and psilocybin (41.4%), with fewer investigating ayahuasca, LSD, ibogaine, salvia divinorum, 5-MeO-DMT, and DMT fumarate. MDMA and psilocybin are primarily studied for PTSD and major depressive disorder; LSD for depression, anxiety, and severe somatic disorders; ibogaine for substance use disorders; and 5-MeO-DMT and DMT for major depressive disorder. Only 21 of the 70 studies had published results; most are ongoing.
Journal of Psychiatric Research
May 1, 2022
Tuyen T. Le, Isabel Pazos Cordero, Muhammad Youshay Jawad et al.
82 citations
Ketamine and its enantiomers show different abuse liability. Preclinical evidence indicates that (R,S)-ketamine and (S)-ketamine carry greater risk for abuse than (R)-ketamine, which at antidepressant-relevant doses in rodents appears safe with minimal liability. In clinical settings, limited studies suggest that single or repeated ketamine administrations under professional control did not lead to misuse, dependence, diversion, or gateway activity in patients with treatment-resistant depression. However, most clinical studies were retrospective and lacked systematic evaluation with validated scales. The review identified 65 eligible studies (55 preclinical, 10 clinical), with only 4 preclinical studies evaluating enantiomer abuse liability.
Journal of Psychiatric Research
May 1, 2022
Timothy D Brewerton, Julie B. Wang, Adele Lafrance et al.
81 citations
Among 89 individuals with severe PTSD enrolled in a placebo-controlled trial of MDMA-assisted therapy, 15% had eating disorder symptoms in the clinical range and 31.5% in the high-risk range at baseline, despite no active purging or low weight. After treatment, participants who received MDMA-assisted therapy showed significantly greater reductions in eating disorder symptoms compared to those who received placebo, especially among women with elevated baseline scores. The findings suggest that eating disorder psychopathology is common in severe PTSD and that MDMA-assisted therapy may reduce these co-occurring symptoms.
Journal of Psychiatric Research
May 1, 2023
Franklin R. Schneier, Jamie D. Feusner, Michael G. Wheaton et al.
79 citations
A single 25 mg oral dose of psilocybin, given with psychological support, significantly reduced body dysmorphic disorder (BDD) symptoms in 12 adults whose condition had not responded to at least one prior serotonin reuptake inhibitor. Over 12 weeks of follow-up, scores on a standard BDD severity scale decreased substantially, with a large effect size and improvements evident from week 1 and sustained through week 12. Seven of 12 participants (58%) showed a 30% or greater reduction in symptoms at week 12. No serious adverse events occurred. These preliminary findings suggest psilocybin may be a promising treatment for BDD, warranting further controlled trials.
Journal of Psychiatric Research
May 1, 2021
Bruno Romeo, Marianne Hermand, Amélie Pétillion et al.
74 citations
A systematic review of 20 studies examined factors predicting response to psychedelic treatments for psychiatric and addictive disorders. The main predictor of a positive response across alcohol and tobacco use disorders, treatment-resistant depression, and anxiety and depressive symptoms in patients with life-threatening cancer was the intensity of the acute psychedelic experience. This factor did not predict response for obsessive-compulsive disorder. Possible mechanisms include modulation of the serotoninergic system via 5-HT2A receptor agonism, disruption and reintegration of the default mode network, or anti-inflammatory effects.
Journal of Psychiatric Research
December 24, 2014
Ke Xu, J. Krystal, Y. Ning et al.
65 citations
Ketamine, a drug that blocks NMDA glutamate receptors, produces symptoms resembling schizophrenia. Analyzing the Positive and Negative Syndrome Scale (PANSS) in four groups—135 healthy people given ketamine or saline, 187 chronic ketamine abusers, 154 early-course schizophrenia patients, and 522 chronic schizophrenia patients—revealed five similar symptom dimensions (positive, negative, cognitive, depressed, excitement/dissociation) across all groups. The chronic ketamine group's symptom structure more closely matched the schizophrenia groups than the acute ketamine group did. Symptoms were milder in ketamine users than in schizophrenia patients (Cohen's d = 0.7). The findings suggest ketamine-induced psychosis shares symptom dimensions with schizophrenia, though confounding factors warrant caution.
Journal of Psychiatric Research
March 1, 2021
Joshua D. Di Vincenzo, Ashley N. Siegel, Orly Lipsitz et al.
59 citations
Most antidepressant medication trials have focused on adults aged 18-65, leaving gaps in knowledge about older and younger populations. Ketamine shows promise for treatment-resistant depression, but its effects in adolescents and older adults are not well understood. This systematic review of 13 studies found that ketamine produced rapid antidepressant effects (within two weeks) in ten studies, with better results from larger, repeated doses and in open-label rather than blinded settings. Two case reports in adolescents noted rapid anti-suicidal effects. Ketamine appeared safe and well-tolerated in these age groups. However, the small number of studies, high heterogeneity, and generally low quality prevent firm conclusions, and rigorous randomized controlled trials are still needed.
Journal of Psychiatric Research
February 10, 2018
Andrew P. Allen, Maura Naughton, J. Dowling et al.
53 citations
Current first-line antidepressants often take weeks to improve symptoms, but low-dose ketamine may work faster, even in treatment-resistant depression. This study compared the effects of ketamine infusion and electroconvulsive therapy (ECT) on biological markers related to stress and inflammation in patients with treatment-resistant depression versus healthy controls. Both treatments improved depressive symptoms. At baseline, patients showed differences in cortisol and kynurenine pathway metabolites compared to controls, though inflammatory markers were similar. After ECT, the cortisol awakening response decreased in responders. Ketamine showed a trend toward reduced kynurenine in responders but did not significantly alter any measured biomarkers.
Journal of Psychiatric Research
September 1, 2018
Li Ren, Jie Deng, S. Min et al.
48 citations
Electroconvulsive therapy (ECT) is highly effective for depression, and ketamine at sub-anesthetic doses also produces rapid antidepressant effects. This systematic review and meta-analysis of 16 randomized controlled trials involving 928 patients examined whether adding ketamine to ECT improves outcomes. At the end of the ECT course, depressive symptoms were not significantly lower in the ketamine group compared to controls. However, depressive scores were lower after the first and after the third through sixth ECT sessions, particularly when ketamine was used as an add-on anesthetic. Ketamine did not improve overall response or remission rates and increased adverse events, especially cardiovascular and psychiatric side effects. Ketamine may accelerate antidepressant effects during ECT but should be used cautiously due to added risks.
Journal of Psychiatric Research
November 1, 2024
Benneth Ben-Azu, Aliance R Fokoua, Olajide S Annafi et al.
24 citations
Silymarin, a polyphenolic flavonoid with neuroprotective functions, prevented and reversed schizophrenia-like behaviors in mice given ketamine, an NMDA antagonist that induces neurochemical dysregulation, neuroimmune stress, and oxidative stress. In a preventive-reversal model, silymarin (50 and 100 mg/kg) reduced ketamine-induced increases in dopamine, serotonin, acetylcholinesterase, malondialdehyde, and nitrite in the striatum, prefrontal cortex, and hippocampus. It improved hyperlocomotion, stereotypy, memory, and social impairments without causing catalepsy. Silymarin also lowered inflammatory markers (myeloperoxidase, tumor-necrosis factor-α, interleukin-6) and normalized decreased brain-derived neurotrophic factor, glutathione, catalase, and superoxide-dismutase levels. The antipsychotic effect may involve normalization of neurochemical and neurotrophic changes.
Journal of Psychiatric Research
May 1, 2024
M Colla, B Offenhammer, H Scheerer et al.
23 citations
A novel oral prolonged-release formulation of racemic ketamine (KET01) was tested as an add-on therapy for treatment-resistant depression. Patients received 160 mg/day, 240 mg/day, or placebo for 14 days. The 240 mg/day group showed a numerically larger but statistically non-significant improvement in depression scores compared to placebo. The trial was terminated early due to poor recruitment during the COVID-19 pandemic, with only 27 patients completing the protocol. Adverse event rates were similar across groups, and no increased risk of suicidality, dissociation, or blood pressure changes was observed. Baseline leukocyte count correlated with response to KET01 in exploratory analysis.
Journal of Psychiatric Research
May 8, 2021
R. Mello, Mariana V F Echegaray, A. P. Jesus-Nunes et al.
22 citations
Dissociative symptoms are common side effects of ketamine and esketamine used for depression. In adults with treatment-resistant depression randomly assigned to a single 40-minute infusion of either esketamine 0.25 mg/kg or ketamine 0.5 mg/kg, those with higher trait dissociation (measured by the Dissociative Experience Scale) had a greater risk of experiencing induced dissociation (measured by the Clinician-Administered Dissociative States Scale). Every 5-point increase in trait dissociation was associated with a 10.9% increase in induced dissociation. Subjects with high trait dissociation had a 1.41 times higher risk of induced dissociation and a 3.05 times higher risk of very high induced dissociation. Induced dissociation was not a serious adverse effect. The findings suggest screening for trait dissociation and counseling patients on risks.
Journal of Psychiatric Research
October 1, 2024
Mohammad-Ali Samizadeh, Seyedeh-Tabassom Abdollahi-Keyvani, Hamed Fallah et al.
21 citations
In a rat model of schizophrenia induced by five daily injections of ketamine (30 mg/kg), recognition memory was impaired and brain-derived neurotrophic factor (BDNF) levels in the prefrontal cortex decreased in both sexes. Ketamine also lowered pain threshold in females, increased rearing behavior in males, and caused greater hyperlocomotion in females. Subsequent treatment with risperidone (2 mg/kg) restored or attenuated all these behavioral effects and BDNF levels. The findings suggest sex differences in how ketamine affects pain perception, locomotion, and rearing behavior in this model.
Journal of Psychiatric Research
August 1, 2024
Noah Chisamore, Danica E. Johnson, Margery J.q. Chen et al.
21 citations
Psilocybin-assisted psychotherapy shows promise for treating depression and distress in life-threatening illnesses, but a systematic review of 28 clinical trial protocols reveals substantial variability and inconsistency in therapeutic approaches beyond the basic framework of preparatory, dosing, and integration sessions. The review found no validated or universally agreed-upon protocol, with frequent lack of clarity in descriptions of therapy models, duration, and number of sessions. Future studies need to define and report psychotherapeutic components more clearly to identify the safest and most effective approaches.
Journal of Psychiatric Research
December 1, 2024
Soroush Oraee, Mohammadreza Alinejadfard, Hossein Golsorkh et al.
13 citations
Intranasal esketamine, given alongside an oral antidepressant, leads to higher remission and response rates than a placebo in people with major depressive disorder, including those with treatment-resistant depression. A meta-analysis of nine clinical trials involving 1,752 patients found that esketamine doses ranging from 28 to 84 mg produced significantly greater remission (risk ratio 1.37) and response (risk ratio 1.27). The 84 mg and flexible doses were particularly effective. Adverse events were common but generally tolerable. The drug appears safe and effective in the short term, though more research is needed on long-term effects and specific patient subgroups.
Journal of Psychiatric Research
November 1, 2023
Hui Kou, Wei Luo, Xinnan Liu et al.
11 citations
Eight weeks of mindfulness training reduced anxiety and depressive symptoms in a non-clinical sample of 80 adults, with effects lasting at least three months. The training also shifted attention: participants became more attentive to happy faces and less attentive to sad faces compared to a control group. The change in attention to sad faces partially explained the reduction in depression immediately after training, but this attentional mechanism played only a limited role in symptom improvement overall. The study suggests mindfulness improves emotional symptoms through multiple pathways, not solely by altering attention to emotional faces.
Journal of Psychiatric Research
December 1, 2024
Lindsey Marwood, Megan Croal, Sunil Mistry et al.
9 citations
In a phase II randomized controlled trial of 233 participants with treatment-resistant depression, those who discontinued antidepressant drugs before receiving psilocybin showed no worsening of depression severity during the discontinuation period, comparable baseline suicidality, and no compromise in psilocybin's treatment efficacy or subjective psychedelic effects relative to those who entered the trial antidepressant-free. The findings suggest that antidepressant discontinuation does not limit the feasibility of psilocybin treatment for treatment-resistant depression and support the homogeneity of psilocybin's effects as a monotherapy.
Journal of Psychiatric Research
October 1, 2024
Zixun Wang, Xinyu Hu, Zhongyi Wang et al.
9 citations
Post-traumatic stress disorder affects 3-4% of people globally each year. In a rat model of PTSD induced by single prolonged stress, a single low dose of ketamine (10 mg/kg) prevented anxiety-like behaviors. Ketamine also reversed stress-induced changes in the hippocampus: it increased expression of glucocorticoid receptor, brain-derived neurotrophic factor, phosphorylated GSK-3β, FKBP5, and CRH, while decreasing GSK-3β protein expression, and it improved synaptic structure. A GSK-3β inhibitor produced similar behavioral effects, suggesting ketamine works by regulating GSK-3β/GR signaling to improve synaptic plasticity.
Journal of Psychiatric Research
August 1, 2024
Eduardo Igor Torquato Cardoso Lopes, Patrícia Cavalcanti-Ribeiro, Fernanda Palhano-Fontes et al.
9 citations
Subcutaneous esketamine injections given weekly for eight weeks produced a rapid and lasting reduction in suicidality among 18 adults with treatment-resistant depression. Suicidal thoughts dropped within 24 hours after the first dose and remained low throughout the eight-week treatment period. At six months after treatment ended, suicidality was still consistently lower. Clinician ratings showed significant improvement only after two sessions, and 61% of patients achieved remission from suicidal ideation. The findings suggest that weekly subcutaneous esketamine may be a cost-effective way to achieve fast and sustained anti-suicide effects, but controlled studies are needed to confirm these initial observations.
Journal of Psychiatric Research
June 1, 2024
Lior Dvorak, Esther Bloemhof-Bris, Assaf Shelef et al.
9 citations
About 60% of patients with treatment-resistant depression who completed an acute phase of esketamine therapy went on to finish a maintenance phase. Depressive symptoms, measured with the Quick Inventory of Depressive Symptomatology, showed linear improvement during both phases. A sub-analysis of patients with a comorbid personality disorder revealed a similar improvement pattern in the acute phase but milder improvement during maintenance compared to other patients. The findings support the use of esketamine for treatment-resistant depression, including for those with comorbid personality disorder or a history of electroconvulsive therapy.
Journal of Psychiatric Research
February 1, 2024
Monique Williams, Cynthia Honan, Sarah Skromanis et al.
9 citations
A systematic review and meta-analysis of five controlled trials (277 participants with elevated trait or generalized anxiety) examined the acute effects of a brief audio-based mindfulness induction on state anxiety and attention. Compared with non-therapeutic control conditions, mindfulness induction produced a medium reduction in state anxiety and a large increase in state mindfulness. Two studies comparing mindfulness to therapeutic active controls also showed small-to-moderate anxiety reductions, though results could not be pooled. Evidence for attention improvements was limited, with one study reporting changes in brain activity in the anterior cingulate cortex. State mindfulness partially mediated anxiety reductions. The small number of studies, high risk of bias, and low certainty of evidence qualify confidence in the findings.
Journal of Psychiatric Research
July 1, 2024
Yecun Liu, Jiguo Yang, Yuanxiang Liu
8 citations
Electroconvulsive therapy (ECT) and ketamine each improve depressive symptoms more than placebo, but ECT appears superior to both ketamine and their combination for reducing depression severity. A network meta-analysis of 17 randomized controlled trials involving 1,370 patients with severe depression found that ECT had the highest probability of being the most effective treatment, followed by the combination of ketamine plus ECT, then ketamine alone, and finally placebo. No significant differences were observed on the Montgomery-Asberg Depression Rating Scale, though rank probabilities again favored ECT. The combination of ketamine and ECT was associated with more adverse reactions, indicating a need for further research on optimal combined use. Individualized treatment decisions remain important.
Journal of Psychiatric Research
July 1, 2023
Mu-Hong Chen, Wei-Chen Lin, Cheng-Ta Li et al.
8 citations
In patients with treatment-resistant depression and strong suicidal thoughts, a single low-dose infusion of ketamine did not change blood levels of two proteins—VEGF and MMP-9—compared to a control drug, midazolam. However, patients who had higher VEGF levels before treatment showed greater improvements in depression and suicidal ideation after ketamine. This suggests that baseline VEGF might help predict who will benefit from ketamine, but the drug itself does not alter these protein levels.