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Treatment of Major Depression

Works Count: 48509

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This cluster of papers focuses on the molecular mechanisms and treatment strategies for depression, with a particular emphasis on antidepressant medications, ketamine, NMDA receptor antagonists, and neurobiological pathways. It covers topics such as treatment-resistant depression, glutamate signaling, cognitive impairment, and synaptic plasticity. The papers also discuss clinical guidelines and the evaluation of outcomes for various treatment approaches.

Keywords

Depression; Antidepressant; Ketamine; NMDA Receptor; Treatment-Resistant Depression; Neurobiological Mechanisms; Glutamate Signaling; Cognitive Impairment; Synaptic Plasticity; Clinical Guidelines

“Mini-mental state”

1975-11-01

Marshal F. Folstein , Susan E. Folstein , Paul R. McHugh

Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex

1997-04-15

Bita Moghaddam , Barbara W. Adams , Anita Verma +1 more

Subanesthetic doses of ketamine, a noncompetitive NMDA receptor antagonist, impair prefrontal cortex (PFC) function in the rat and produce symptoms in humans similar to those observed in schizophrenia and dissociative … Subanesthetic doses of ketamine, a noncompetitive NMDA receptor antagonist, impair prefrontal cortex (PFC) function in the rat and produce symptoms in humans similar to those observed in schizophrenia and dissociative states, including impaired performance of frontal lobe-sensitive tests. Several lines of evidence suggest that ketamine may impair PFC function in part by interacting with dopamine neurotransmission in this region. This study sought to determine the mechanism by which ketamine may disrupt dopaminergic neurotransmission in, and cognitive functions associated with, the PFC. A thorough dose-response study using microdialysis in conscious rats indicated that low doses of ketamine (10, 20, and 30 mg/kg) increase glutamate outflow in the PFC, suggesting that at these doses ketamine may increase glutamatergic neurotransmission in the PFC at non-NMDA glutamate receptors. An anesthetic dose of ketamine (200 mg/kg) decreased, and an intermediate dose of 50 mg/kg did not affect, glutamate levels. Ketamine, at 30 mg/kg, also increased the release of dopamine in the PFC. This increase was blocked by intra-PFC application of the AMPA/kainate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione CNQX. Furthermore, ketamine-induced activation of dopamine release and impairment of spatial delayed alternation in the rodent, a PFC-sensitive cognitive task, was ameliorated by systemic pretreatment with AMPA/kainate receptor antagonist LY293558. These findings suggest that ketamine may disrupt dopaminergic neurotransmission in the PFC as well as cognitive functions associated with this region, in part, by increasing the release of glutamate, thereby stimulating postsynaptic non-NMDA glutamate receptors.

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The 16-Item quick inventory of depressive symptomatology (QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): a psychometric evaluation in patients with chronic major depression

2003-04-23

A. John Rush , Madhukar H. Trivedi , Hicham M. Ibrahim +7 more

Norepinephrine in Depressive Reactions

1965-12-01

William E. Bunney

<h3>Introduction</h3> LITTLE IS known about the possible etiological biochemical factors relating to depressive reactions. Clinical evidence suggests that many depressions respond to the following somatic treatment: electric convulsive therapy (ECT), … <h3>Introduction</h3> LITTLE IS known about the possible etiological biochemical factors relating to depressive reactions. Clinical evidence suggests that many depressions respond to the following somatic treatment: electric convulsive therapy (ECT), the imipramine type of drugs, and the monoamine oxidase inhibitor group of drugs.<sup>2,3</sup>Do these two classes of drugs have common factors in their mechanism of action and can this be related to the fact that one antihypertensive agent, namely, reserpine, produces severe depression in a small but consistent number of hypertensive patients?<sup>4-8</sup> Rosenblatt et al,<sup>9</sup>in 1959, were among the first to specifically suggest that changes in brain norepinephrine (NEP) may be involved in depression. Based in part on the knowledge of the effect of reserpine and monoamine oxidase inhibitors on depressed mood and norepinephrine (NEP), they hypothesized that the depressive state might be associated with a relative decrease of norepinephrine

Glutamate N-methyl-D-aspartate Receptor Antagonists Rapidly Reverse Behavioral and Synaptic Deficits Caused by Chronic Stress Exposure

2011-02-04

Nanxin Li , Rong-Jian Liu , Jason M. Dwyer +6 more

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NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses

2011-06-14

Anita E. Autry , Megumi Adachi , E. D. Nosyreva +5 more

Medication Augmentation after the Failure of SSRIs for Depression

2006-03-22

Madhukar H. Trivedi , Maurizio Fava , Stephen R. Wisniewski +7 more

Although clinicians frequently add a second medication to an initial, ineffective antidepressant drug, no randomized controlled trial has compared the efficacy of this approach. Although clinicians frequently add a second medication to an initial, ineffective antidepressant drug, no randomized controlled trial has compared the efficacy of this approach.

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Current advances and trends in the treatment of depression

1994-07-01

Pierre Blier , Claude de Montigny

Regional metabolic effects of fluoxetine in major depression: serial changes and relationship to clinical response

2000-10-01

Helen S. Mayberg , Steven Brannan , Janet L. Tekell +4 more

Antidepressant Drug Effects and Depression Severity

2010-01-05

Jay C. Fournier , Robert J. DeRubeis , Steven D. Hollon +4 more

Antidepressant medications represent the best established treatment for major depressive disorder, but there is little evidence that they have a specific pharmacological effect relative to pill placebo for patients with … Antidepressant medications represent the best established treatment for major depressive disorder, but there is little evidence that they have a specific pharmacological effect relative to pill placebo for patients with less severe depression.

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Ketamine—Its Pharmacology and Therapeutic Uses

1982-02-01

Paul F. White , Walter L. Way , Anthony J. Trevor

Ketamine—Its Pharmacology and Therapeutic Uses Paul white;Walter Way;anthony Trevor; Anesthesiology Ketamine—Its Pharmacology and Therapeutic Uses Paul white;Walter Way;anthony Trevor; Anesthesiology

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Psychopharmacology: The Fourth Generation of Progress

1995-12-13

James J. Brophy

The number 2002 has various connotations in our current thinking: the year of a balanced budget and Medicare bankruptcy. But in the realm of psychopharmacology, 2002 is the number of … The number 2002 has various connotations in our current thinking: the year of a balanced budget and Medicare bankruptcy. But in the realm of psychopharmacology, 2002 is the number of pages in the latest edition of this definitive book on the subject. At 11 lbs it is a behemoth, but the material therein is an argosy of medical information. It is a major advance over the very good previous edition,<i>Psychopharmacology: The Third Generation of Progress</i>, reviewed in<i>JAMA</i>(1988;259:1392). The 317 contributors from around the world include the best and the brightest minds from the fields of academic and commercial psychopharmacology. Of the 163 chapters, approximately one third deal with the preclinical issues and the remainder with clinical disorders. Subject material extends far beyond the field of psychopharmacology. The use of imaging techniques is not only discussed separately, but also permeates the discussions of both research and clinical issues.

Randomized trial of behavioral activation, cognitive therapy, and antidepressant medication in the acute treatment of adults with major depression.

2006-01-01

Sona Dimidjian , Steven D. Hollon , Keith S. Dobson +7 more

Antidepressant medication is considered the current standard for severe depression, and cognitive therapy is the most widely investigated psychosocial treatment for depression. However, not all patients want to take medication, … Antidepressant medication is considered the current standard for severe depression, and cognitive therapy is the most widely investigated psychosocial treatment for depression. However, not all patients want to take medication, and cognitive therapy has not demonstrated consistent efficacy across trials. Moreover, dismantling designs have suggested that behavioral components may account for the efficacy of cognitive therapy. The present study tested the efficacy of behavioral activation by comparing it with cognitive therapy and antidepressant medication in a randomized placebo-controlled design in adults with major depressive disorder (N = 241). In addition, it examined the importance of initial severity as a moderator of treatment outcome. Among more severely depressed patients, behavioral activation was comparable to antidepressant medication, and both significantly outperformed cognitive therapy. The implications of these findings for the evaluation of current treatment guidelines and dissemination are discussed.

Antidepressant effects of ketamine in depressed patients

2000-02-01

Robert Berman , Angela Cappiello , Amit Anand +4 more

Sequenced treatment alternatives to relieve depression (STAR*D): rationale and design

2004-02-01

A. John Rush , Maurizio Fava , Stephen R. Wisniewski +7 more

Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans

1994-03-01

John H. Krystal

<h3>Background:</h3> To characterize further behavioral, cognitive, neuroendocrine, and physiological effects of subanesthetic doses of ketamine hydrochloride in healthy human subjects. Ketamine, a phencyclidine hydrochloride derivative, is a dissociative anesthetic and … <h3>Background:</h3> To characterize further behavioral, cognitive, neuroendocrine, and physiological effects of subanesthetic doses of ketamine hydrochloride in healthy human subjects. Ketamine, a phencyclidine hydrochloride derivative, is a dissociative anesthetic and a noncompetitive antagonist of the<i>N</i>-methyl-D-aspartate subtype of excitatory amino acid receptor. <h3>Methods:</h3> Nineteen healthy subjects recruited by advertisements from the community participated in this randomized, double-blind, placebo-controlled study. Subjects completed three test days involving the 40-minute intravenous administration of placebo, ketamine hydrochloride (0.1 mg/kg), or ketamine hydrochloride (0.5 mg/kg). Behaviors associated with the positive and negative symptoms of schizophrenia were assessed by using the Brief Psychiatric Rating Scale. Changes in perception and behaviors associated with dissociative states were assessed by the Perceptual Aberration Subscale of the Wisconsin Psychosis Proneness Scale and the Clinician-Administered Dissociative States Scale. Cognitive function was assessed by using the (1) Mini-Mental State Examination; (2) tests sensitive to frontal cortical dysfunction, including a continuous performance vigilance task, a verbal fluency task, and the Wisconsin Card Sorting Test; and (3) tests of immediate and delayed recall. Plasma levels of cortisol, prolactin, homovanillic acid, and 3-methoxy-4-hydroxyphenethyleneglycol were measured. <h3>Results:</h3> Ketamine (1) produced behaviors similar to the positive and negative symptoms of schizophrenia; (2) elicited alterations in perception; (3) impaired performance on tests of vigilance, verbal fluency, and the Wisconsin Card Sorting Test; (4) evoked symptoms similar to dissociative states; and (5) preferentially disrupted delayed word recall, sparing immediate recall and postdistraction recall. Ketamine had no significant effect on the Mini-Mental State Examination at the doses studied. Ketamine also had no effect on plasma 3-methoxy-4hydroxyphenethyleneglycol levels, although it blunted a test day decline in plasma homovanillic acid levels at the higher dose. It also dose dependently increased plasma cortisol and prolactin levels. Ketamine produced small dose-dependent increases in blood pressure. <h3>Conclusions:</h3> These data indicate that<i>N</i>-methyl-Daspartate antagonists produce a broad range of symptoms, behaviors, and cognitive deficits that resemble aspects of endogenous psychoses, particularly schizophrenia and dissociative states.

Cellular Mechanisms Underlying the Antidepressant Effects of Ketamine: Role of α-Amino-3-Hydroxy-5-Methylisoxazole-4-Propionic Acid Receptors

2007-07-24

Sungho Maeng , Carlos A. Zarate , Jing Du +4 more

Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression∗∗See accompanying Editorial, in this issue.

1999-05-01

Grażyna Rajkowska , José Javier Miguel-Hidalgo , Jinrong Wei +6 more

St John's wort for depression--an overview and meta-analysis of randomised clinical trials

1996-08-03

Klaus Linde , Gilbert Ramı́rez , Cynthia D. Mulrow +3 more

<h3>Abstract</h3> <b>Objective</b>: To investigate if extracts of Hypericum perforatum (St John9s wort) are more effective than placebo in the treatment of depression, are as effective as standard antidepressive treatment, and … <h3>Abstract</h3> <b>Objective</b>: To investigate if extracts of Hypericum perforatum (St John9s wort) are more effective than placebo in the treatment of depression, are as effective as standard antidepressive treatment, and have fewer side effects than standard antidepressant drugs. <b>Design</b>: Systematic review and meta-analysis of trials revealed by searches. <b>Trials</b>: 23 randomised trials including a total of 1757 outpatients with mainly mild or moderately severe depressive disorders: 15 (14 testing single preparations and one a combination with other plant extracts) were placebo controlled, and eight (six testing single preparations and two combinations) compared hypericum with another drug treatment. <b>Main outcome measures</b>: A pooled estimate of the responder rate ratio (responder rate in treatment group/responder rate in control group), and numbers of patients reporting and dropping out for side effects. <b>Results</b>: Hypericum extracts were significantly superior to placebo (ratio = 2.67; 95% confidence interval 1.78 to 4.01) and similarly effective as standard antidepressants (single preparations 1.10; 0.93 to 1.31, combinations 1.52; 0.78 to 2.94). There were two (0.8%) drop outs for side effects with hypericum and seven (3.0%) with standard antidepressant drugs. Side effects occurred in 50 (19.8%) patients on hypericum and 84 (52.8%) patients on standard antidepressants. <b>Conclusion</b>: There is evidence that extracts of hypericum are more effective than placebo for the treatment of mild to moderately severe depressive disorders. Further studies comparing extracts with standard antidepressants in well defined groups of patients and comparing different extracts and doses are needed. <h3>Key messages</h3> There is evidence from randomised trials that such extracts are more effective than placebo for the treatment of depressive disorders, but it is not known whether they are more effective for certain disorders than others Current evidence is inadequate to establish whether hypericum is as effective as other antidepressants and if it has fewer side effects Additional trials should be conducted to compare hypericum with other antidepressants in well defined groups of patients; to investigate long term side effects; and to evaluate the relative efficacy of different preparations and doses

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Diagnosis and definition of treatment-resistant depression

2003-04-01

Maurizio Fava

Psychopharmacology: The third generation of progress

1988-05-01

Ralph A. O’Connell

Screening Tests for Geriatric Depression

1982-10-14

T. L. Brink , Jerome A. Yesavage , Owen Lum +3 more

Contends that the diagnosis of depression in aged patients is the responsibility of both psychologists, and non-psychologists, for it is the latter that is most likely to make initial contact … Contends that the diagnosis of depression in aged patients is the responsibility of both psychologists, and non-psychologists, for it is the latter that is most likely to make initial contact with an elder in need of help. Describes problems in the use of psychometric tests to identify geriatric depression. Reviews the advantages and disadvantages and limitations of scales currently employed. Introduces a new Geriatric Depression Scale and demonstrates how it compares favorably with the Zung and Hamilton scales. Suggests appropriate cutoff scores on each of the three scales when they are used with older patients.

Severity classification on the Hamilton depression rating scale

2013-06-04

Mark Zimmerman , Jennifer H. Martinez , Diane Young +2 more

mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists

2010-08-19

Nanxin Li , Boyoung Lee , Rongjian Liu +6 more

Antidepressant Action of Ketamine In contrast to the weeks or months of treatment required for standard antidepressant medication, ketamine administration produces an antidepressant response within 4 to 6 hours in … Antidepressant Action of Ketamine In contrast to the weeks or months of treatment required for standard antidepressant medication, ketamine administration produces an antidepressant response within 4 to 6 hours in depressed patients. What lies behind the rapid actions of ketamine? Li et al. (p. 959 ; see the Perspective by Cryan and O'Leary ) found that ketamine administration resulted in fast activation of mammalian target of rapamycin (mTOR) signaling and increased levels of synaptic proteins in the rat prefrontal cortex. Ketamine rapidly increased the density and function of the dendritic spines of layer V pyramidal neurons in the prefrontal cortex. Thus, the behavioral actions of ketamine in models of depression and antidepressant response are dependent on mTOR signaling.

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Major depressive disorder is associated with broad impairments on neuropsychological measures of executive function: A meta-analysis and review.

2012-05-30

Hannah R. Snyder

Cognitive impairments are now widely acknowledged as an important aspect of major depressive disorder (MDD), and it has been proposed that executive function (EF) may be particularly impaired in patients … Cognitive impairments are now widely acknowledged as an important aspect of major depressive disorder (MDD), and it has been proposed that executive function (EF) may be particularly impaired in patients with MDD.However, the existence and nature of EF impairments associated with depression remain strongly debated.While many studies have found significant deficits associated with MDD on neuropsychological measures of EF, others have not, potentially due to low statistical power, task impurity, and diverse patient samples, and there have been no recent, comprehensive, meta-analyses investigating EF in patients with MDD.The current meta-analysis uses random effects models to synthesize 113 previous research studies that compared participants with MDD to healthy control participants on at least one neuropsychological measure of EF. Results of the meta-analysis demonstrate that MDD is reliably associated with impaired performance on neuropsychological measures of EF, with effect sizes ranging from d = 0.32-0.97.While patients with MDD also have slower processing speed, motor slowing alone cannot account for these results.In addition, some evidence suggests that deficits on neuropsychological measures of EF are greater in patients with more severe current depression symptoms, and those taking psychotropic medications, while evidence for effects of age was weaker.The results are consistent with the theory that MDD is associated with broad impairment in multiple aspects of EF.Implications for treatment of MDD and theories of EF are discussed.Future research is needed to establish the specificity and causal link between MDD and EF impairments.

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Three-Year Outcomes for Maintenance Therapies in Recurrent Depression

1990-12-01

David J. Kupfer , Ellen Frank , James M. Perel +5 more

• We conducted a randomized 3-year maintenance trial in 128 patients with recurrent depression who had responded to combined short-term and continuation treatment with imipramine hydrochloride and interpersonal psychotherapy. A … • We conducted a randomized 3-year maintenance trial in 128 patients with recurrent depression who had responded to combined short-term and continuation treatment with imipramine hydrochloride and interpersonal psychotherapy. A five-cell design was used to determine whether a maintenance form of interpersonal psychotherapy alone or in combination with medication could play a significant role in the prevention of recurrence. A second question was whether maintaining antidepressant medication at the dosage used to treat the acute episode rather than decreasing to a "maintenance" dosage would provide prophylaxis superior to that observed in earlier trials in which a maintenance dosage strategy was employed. Survival analysis demonstrated a highly significant prophylactic effect for active imipramine hydrochloride maintained at an average dose of 200 mg and a modest prophylactic effect for monthly interpersonal psychotherapy. We conclude that active imipramine hydrochloride maintained at an average dose of 200 mg is an effective means of preventing recurrence and that monthly interpersonal psychotherapy serves to lengthen the time between episodes in patients not receiving active medication.

Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised

1988-01-01

Thomas P. Kobylski

A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression

2006-08-01

Carlos A. Zarate , Jaskaran Singh , Paul J. Carlson +5 more

<h3>Context</h3> Existing therapies for major depression have a lag of onset of action of several weeks, resulting in considerable morbidity. Exploring pharmacological strategies that have rapid onset of antidepressant effects … <h3>Context</h3> Existing therapies for major depression have a lag of onset of action of several weeks, resulting in considerable morbidity. Exploring pharmacological strategies that have rapid onset of antidepressant effects within a few days and that are sustained would have an enormous impact on patient care. Converging lines of evidence suggest the role of the glutamatergic system in the pathophysiology and treatment of mood disorders. <h3>Objective</h3> To determine whether a rapid antidepressant effect can be achieved with an antagonist at the<i>N</i>-methyl-D-aspartate receptor in subjects with major depression. <h3>Design</h3> A randomized, placebo-controlled, double-blind crossover study from November 2004 to September 2005. <h3>Setting</h3> Mood Disorders Research Unit at the National Institute of Mental Health. <h3>Patients</h3> Eighteen subjects with<i>DSM-IV</i>major depression (treatment resistant). <h3>Interventions</h3> After a 2-week drug-free period, subjects were given an intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on 2 test days, a week apart. Subjects were rated at baseline and at 40, 80, 110, and 230 minutes and 1, 2, 3, and 7 days postinfusion. <h3>Main Outcome Measure</h3> Changes in scores on the primary efficacy measure, the 21-item Hamilton Depression Rating Scale. <h3>Results</h3> Subjects receiving ketamine showed significant improvement in depression compared with subjects receiving placebo within 110 minutes after injection, which remained significant throughout the following week. The effect size for the drug difference was very large (d = 1.46 [95% confidence interval, 0.91-2.01]) after 24 hours and moderate to large (d = 0.68 [95% confidence interval, 0.13-1.23]) after 1 week. Of the 17 subjects treated with ketamine, 71% met response and 29% met remission criteria the day following ketamine infusion. Thirty-five percent of subjects maintained response for at least 1 week. <h3>Conclusions</h3> Robust and rapid antidepressant effects resulted from a single intravenous dose of an<i>N</i>-methyl-D-aspartate antagonist; onset occurred within 2 hours postinfusion and continued to remain significant for 1 week. <h3>Trial Registration</h3> clinicaltrials.gov Identifier:NCT00088699.

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Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial

2013-08-28

James W. Murrough , Dan V. Iosifescu , Lee C. Chang +7 more

Intravenous ketamine demonstrated rapid antidepressant effects in an optimized study design, improving depression severity in 64% of treatment-resistant patients 24 hours after a single dose. The double-blind trial provides evidence … Intravenous ketamine demonstrated rapid antidepressant effects in an optimized study design, improving depression severity in 64% of treatment-resistant patients 24 hours after a single dose. The double-blind trial provides evidence for the role of the N-methyl-d-aspartate glutamate receptor in depression, a receptor not currently activated by existing antidepressant drugs.

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A New Depression Scale Designed to be Sensitive to Change

1979-04-01

Stuart Montgomery , Marie Åsberg

Summary The construction of a depression rating scale designed to be particularly sensitive to treatment effects is described. Ratings of 54 English and 52 Swedish patients on a 65 item … Summary The construction of a depression rating scale designed to be particularly sensitive to treatment effects is described. Ratings of 54 English and 52 Swedish patients on a 65 item comprehensive psychopathology scale were used to identify the 17 most commonly occurring symptoms in primary depressive illness in the combined sample. Ratings on these 17 items for 64 patients participating in studies of four different antidepressant drugs were used to create a depression scale consisting of the 10 items which showed the largest changes with treatment and the highest correlation to overall change. The inter-rater reliability of the new depression scale was high. Scores on the scale correlated significantly with scores on a standard rating scale for depression, the Hamilton Rating Scale (HRS), indicating its validity as a general severity estimate. Its capacity to differentiate between responders and non-responders to antidepressant treatment was better than the HRS, indicating greater sensitivity to change. The practical and ethical implications in terms of smaller sample sizes in clinical trials are discussed.

Acute and Longer-Term Outcomes in Depressed Outpatients Requiring One or Several Treatment Steps: A STAR*D Report

2006-11-01

A. John Rush , Madhukar H. Trivedi , Stephen R. Wisniewski +7 more

Objective: This report describes the participants and compares the acute and longer-term treatment outcomes associated with each of four successive steps in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) … Objective: This report describes the participants and compares the acute and longer-term treatment outcomes associated with each of four successive steps in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. Method: A broadly representative adult outpatient sample with nonpsychotic major depressive disorder received one (N=3,671) to four (N=123) successive acute treatment steps. Those not achieving remission with or unable to tolerate a treatment step were encouraged to move to the next step. Those with an acceptable benefit, preferably symptom remission, from any particular step could enter a 12-month naturalistic follow-up phase. A score of ≤5 on the Quick Inventory of Depressive Symptomatology–Self-Report (QIDS-SR 16 ) (equivalent to ≤7 on the 17-item Hamilton Rating Scale for Depression [HRSD 17 ]) defined remission; a QIDS-SR 16 total score of ≥11 (HRSD 17 ≥14) defined relapse. Results: The QIDS-SR 16 remission rates were 36.8%, 30.6%, 13.7%, and 13.0% for the first, second, third, and fourth acute treatment steps, respectively. The overall cumulative remission rate was 67%. Overall, those who required more treatment steps had higher relapse rates during the naturalistic follow-up phase. In addition, lower relapse rates were found among participants who were in remission at follow-up entry than for those who were not after the first three treatment steps. Conclusions: When more treatment steps are required, lower acute remission rates (especially in the third and fourth treatment steps) and higher relapse rates during the follow-up phase are to be expected. Studies to identify the best multistep treatment sequences for individual patients and the development of more broadly effective treatments are needed.

Cognitive Therapy for Depression

2012-01-01

Steven D. Hollon , Aaron T. Beck

We provide an overview of cognitive therapy (CT) of depression, including its treatment procedures, therapeutic effects, and mechanisms of change, as well as its effectiveness and dissemination. CT is a … We provide an overview of cognitive therapy (CT) of depression, including its treatment procedures, therapeutic effects, and mechanisms of change, as well as its effectiveness and dissemination. CT is a well-established treatment with acute effects on par with those of medication. Unlike medication, CT appears to have effects that endure after treatment ends. Although definitively establishing CT’s mechanism of action is difficult, the available evidence is consistent with the possibility that CT achieves its effects partly through cognitive change. Despite potential challenges in generalizing research findings on CT into clinical practice, initial evidence of the effectiveness of CT has been promising. Finally, we discuss efforts to disseminate CT, along with our thoughts on future research directions.

The Epidemiology of Major Depressive Disorder

2003-06-18

Ronald C. Kessler , Patricia A. Berglund , Olga Demler +6 more

ContextUncertainties exist about prevalence and correlates of major depressive disorder (MDD).ObjectiveTo present nationally representative data on prevalence and correlates of MDD by Diagnostic and Statistical Manual of Mental Disorders, Fourth … ContextUncertainties exist about prevalence and correlates of major depressive disorder (MDD).ObjectiveTo present nationally representative data on prevalence and correlates of MDD by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria, and on study patterns and correlates of treatment and treatment adequacy from the recently completed National Comorbidity Survey Replication (NCS-R).DesignFace-to-face household survey conducted from February 2001 to December 2002.SettingThe 48 contiguous United States.ParticipantsHousehold residents ages 18 years or older (N = 9090) who responded to the NCS-R survey.Main Outcome MeasuresPrevalence and correlates of MDD using the World Health Organization's (WHO) Composite International Diagnostic Interview (CIDI), 12-month severity with the Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR), the Sheehan Disability Scale (SDS), and the WHO disability assessment scale (WHO-DAS). Clinical reinterviews used the Structured Clinical Interview for DSM-IV.ResultsThe prevalence of CIDI MDD for lifetime was 16.2% (95% confidence interval [CI], 15.1-17.3) (32.6-35.1 million US adults) and for 12-month was 6.6% (95% CI, 5.9-7.3) (13.1-14.2 million US adults). Virtually all CIDI 12-month cases were independently classified as clinically significant using the QIDS-SR, with 10.4% mild, 38.6% moderate, 38.0% severe, and 12.9% very severe. Mean episode duration was 16 weeks (95% CI, 15.1-17.3). Role impairment as measured by SDS was substantial as indicated by 59.3% of 12-month cases with severe or very severe role impairment. Most lifetime (72.1%) and 12-month (78.5%) cases had comorbid CIDI/DSM-IV disorders, with MDD only rarely primary. Although 51.6% (95% CI, 46.1-57.2) of 12-month cases received health care treatment for MDD, treatment was adequate in only 41.9% (95% CI, 35.9-47.9) of these cases, resulting in 21.7% (95% CI, 18.1-25.2) of 12-month MDD being adequately treated. Sociodemographic correlates of treatment were far less numerous than those of prevalence.ConclusionsMajor depressive disorder is a common disorder, widely distributed in the population, and usually associated with substantial symptom severity and role impairment. While the recent increase in treatment is encouraging, inadequate treatment is a serious concern. Emphasis on screening and expansion of treatment needs to be accompanied by a parallel emphasis on treatment quality improvement.

Bupropion-SR, Sertraline, or Venlafaxine-XR after Failure of SSRIs for Depression

2006-03-22

A. John Rush , Madhukar H. Trivedi , Stephen R. Wisniewski +7 more

After unsuccessful treatment for depression with a selective serotonin-reuptake inhibitor (SSRI), it is not known whether switching to one antidepressant is more effective than switching to another.We randomly assigned 727 … After unsuccessful treatment for depression with a selective serotonin-reuptake inhibitor (SSRI), it is not known whether switching to one antidepressant is more effective than switching to another.We randomly assigned 727 adult outpatients with a nonpsychotic major depressive disorder who had no remission of symptoms or could not tolerate the SSRI citalopram to receive one of the following drugs for up to 14 weeks: sustained-release bupropion (239 patients) at a maximal daily dose of 400 mg, sertraline (238 patients) at a maximal daily dose of 200 mg, or extended-release venlafaxine (250 patients) at a maximal daily dose of 375 mg. The study was conducted in 18 primary and 23 psychiatric care settings. The primary outcome was symptom remission, defined by a total score of 7 or less on the 17-item Hamilton Rating Scale for Depression (HRSD-17) at the end of the study. Scores on the Quick Inventory of Depressive Symptomatology - Self Report (QIDS-SR-16), obtained at treatment visits, determined secondary outcomes, including remission (a score of 5 or less at exit) and response (a reduction of 50 percent or more on baseline scores).Remission rates as assessed by the HRSD-17 and the QIDS-SR-16, respectively, were 21.3 percent and 25.5 percent for sustained-release bupropion, 17.6 percent and 26.6 percent for sertraline, and 24.8 percent and 25.0 percent for extended-release venlafaxine. QIDS-SR-16 response rates were 26.1 percent for sustained-release bupropion, 26.7 percent for sertraline, and 28.2 percent for extended-release venlafaxine. These treatments did not differ significantly with respect to outcomes, tolerability, or adverse events.After unsuccessful treatment with an SSRI, approximately one in four patients had a remission of symptoms after switching to another antidepressant. Any one of the medications in the study provided a reasonable second-step choice for patients with depression. (ClinicalTrials.gov number, NCT00021528.).

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Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis

2009-01-29

Andrea Cipriani , Toshi A. Furukawa , Georgia Salanti +7 more

Evaluation of Outcomes With Citalopram for Depression Using Measurement-Based Care in STAR*D: Implications for Clinical Practice

2006-01-01

Madhukar H. Trivedi , A. John Rush , Stephen R. Wisniewski +7 more

Selective serotonin reuptake inhibitors (SSRIs) are widely used to treat depression, but the rates, timing, and baseline predictors of remission in "real world" patients are not established. The authors' primary … Selective serotonin reuptake inhibitors (SSRIs) are widely used to treat depression, but the rates, timing, and baseline predictors of remission in "real world" patients are not established. The authors' primary objectives in this study were to evaluate the effectiveness of citalopram, an SSRI, using measurement-based care in actual practice, and to identify predictors of symptom remission in outpatients with major depressive disorder.This clinical study included outpatients with major depressive disorder who were treated in 23 psychiatric and 18 primary care "real world" settings. The patients received flexible doses of citalopram prescribed by clinicians for up to 14 weeks. The clinicians were assisted by a clinical research coordinator in the application of measurement-based care, which included the routine measurement of symptoms and side effects at each treatment visit and the use of a treatment manual that described when and how to modify medication doses based on these measures. Remission was defined as an exit score of <or=7 on the 17-item Hamilton Depression Rating Scale (HAM-D) (primary outcome) or a score of <or=5 on the 16-item Quick Inventory of Depressive Symptomatology, Self-Report (QIDS-SR) (secondary outcome). Response was defined as a reduction of >or=50% in baseline QIDS-SR score.Nearly 80% of the 2,876 outpatients in the analyzed sample had chronic or recurrent major depression; most also had a number of comorbid general medical and psychiatric conditions. The mean exit citalopram dose was 41.8 mg/day. Remission rates were 28% (HAM-D) and 33% (QIDS-SR). The response rate was 47% (QIDS-SR). Patients in primary and psychiatric care settings did not differ in remission or response rates. A substantial portion of participants who achieved either response or remission at study exit did so at or after 8 weeks of treatment. Participants who were Caucasian, female, employed, or had higher levels of education or income had higher HAM-D remission rates; longer index episodes, more concurrent psychiatric disorders (especially anxiety disorders or drug abuse), more general medical disorders, and lower baseline function and quality of life were associated with lower HAM-D remission rates.The response and remission rates in this highly generalizable sample with substantial axis I and axis III comorbidity closely resemble those seen in 8-week efficacy trials. The systematic use of easily implemented measurement-based care procedures may have assisted in achieving these results.

Cognitive impairment in depression: a systematic review and meta-analysis

2013-10-29

P L Rock , Jonathan P. Roiser , Wim J. Riedel +1 more

Background This review aimed to address the question of whether cognitive impairment should be considered a core feature of depression that may be a valuable target for treatment. Method We … Background This review aimed to address the question of whether cognitive impairment should be considered a core feature of depression that may be a valuable target for treatment. Method We conducted a systematic review and meta-analysis of cognitive function, assessed with a single neuropsychological test battery, the Cambridge Neuropsychological Test Automated Battery (CANTAB), in patients with depression during symptomatic and remitted states. Inclusion of studies comparing patients remitted from depression and controls enabled us to investigate whether cognitive impairment persists beyond episodes of low mood in depression. Results Our meta-analysis revealed significant moderate cognitive deficits in executive function, memory and attention in patients with depression relative to controls (Cohen's d effect sizes ranging from −0.34 to −0.65). Significant moderate deficits in executive function and attention (Cohen's d ranging from −0.52 to −0.61) and non-significant small/moderate deficits in memory (Cohen's d ranging from −0.22 to −0.54) were found to persist in patients whose depressive symptoms had remitted, indicating that cognitive impairment occurs separately from episodes of low mood in depression. Conclusions Both low mood and cognitive impairment are associated with poor psychosocial functioning. Therefore, we argue that remediation of cognitive impairment and alleviation of depressive symptoms each play an important role in improving outcome for patients with depression. In conclusion, this systematic review and meta-analysis demonstrates that cognitive impairment represents a core feature of depression that cannot be considered an epiphenomenon that is entirely secondary to symptoms of low mood and that may be a valuable target for future interventions.

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Synaptic Dysfunction in Depression: Potential Therapeutic Targets

2012-10-04

Ronald S. Duman , George K. Aghajanian

Basic and clinical studies demonstrate that depression is associated with reduced size of brain regions that regulate mood and cognition, including the prefrontal cortex and the hippocampus, and decreased neuronal … Basic and clinical studies demonstrate that depression is associated with reduced size of brain regions that regulate mood and cognition, including the prefrontal cortex and the hippocampus, and decreased neuronal synapses in these areas. Antidepressants can block or reverse these neuronal deficits, although typical antidepressants have limited efficacy and delayed response times of weeks to months. A notable recent discovery shows that ketamine, a N -methyl- d -aspartate receptor antagonist, produces rapid (within hours) antidepressant responses in patients who are resistant to typical antidepressants. Basic studies show that ketamine rapidly induces synaptogenesis and reverses the synaptic deficits caused by chronic stress. These findings highlight the central importance of homeostatic control of mood circuit connections and form the basis of a synaptogenic hypothesis of depression and treatment response.

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A Structured Interview Guide for the Hamilton Depression Rating Scale

1988-08-01

Janet B. W. Williams

• The Hamilton Depression Rating Scale (HDRS) is the most widely used scale for patient selection and follow-up in research studies of treatments of depression. Despite extensive study of the … • The Hamilton Depression Rating Scale (HDRS) is the most widely used scale for patient selection and follow-up in research studies of treatments of depression. Despite extensive study of the reliability and validity of the total scale score, the psychometric characteristics of the individual items have not been well studied. In the only reliability study to report agreement on individual items using a test-retest interview method, most of the items had only fair or poor agreement. Because this is due in part to variability in the way the Information is obtained to make the various rating distinctions, the Structured Interview Guide for the HDRS (SIGH-D) was developed to standardize the manner of administration of the scale. A test-retest reliability study conducted on a series of psychiatric inpatients demonstrated that the use of the SIGH-D results in a substantially improved level of agreement for most of the HDRS items.

National Institute of Mental Health Treatment of Depression Collaborative Research Program

1989-11-01

Irene Elkin , M. Tracie Shea , John T. Watkins +7 more

• We investigated the effectiveness of two brief psychotherapies, interpersonal psychotherapy and cognitive behavior therapy, for the treatment of outpatients with major depressive disorder diagnosed by Research Diagnostic Criteria. Two … • We investigated the effectiveness of two brief psychotherapies, interpersonal psychotherapy and cognitive behavior therapy, for the treatment of outpatients with major depressive disorder diagnosed by Research Diagnostic Criteria. Two hundred fifty patients were randomly assigned to one of four 16-week treatment conditions: interpersonal psychotherapy, cognitive behavior therapy, imipramine hydrochloride plus clinical management (as a standard reference treatment), and placebo plus clinical management. Patients in all treatments showed signifi-cant reduction in depressive symptoms and improvement in functioning over the course of treatment. There was a consistent ordering of treatments at termination, with imipramine plus clinical management generally doing best, placebo plus clinical management worst, and the two psychotherapies in between but generally closer to imipramine plus clinical management. In analyses carried out on the total samples without regard to initial severity of illness (the primary analyses), there was no evidence of greater effectiveness of one of the psychotherapies as compared with the other and no evidence that either of the psychotherapies was significantly less effective than the standard reference treatment, imipramine plus clinical management. Comparing each of the psychotherapies with the placebo plus clinical management condition, there was limited evidence of the specific effectiveness of interpersonal psychotherapy and none for cognitive behavior therapy. Superior recovery rates were found for both interpersonal psychotherapy and imipramine plus clinical management, as compared with placebo plus clinical management. On mean scores, however, there were few significant differences in effectiveness among the four treatments in the primary analyses. Secondary analyses, in which patients were dichotomized on intial level of severity of depressive symptoms and impairment of functioning, helped to explain the relative lack of significant findings in the primary analyses. Significant differences among treatments were present only for the subgroup of patients who were more severely depressed and functionally impaired; here, there was some evidence of the effectiveness of interpersonal psychotherapy with these patients and strong evidence of the effectiveness of imipramine plus clinical management. In contrast, there were no significant differences among treatments, including placebo plus clinical management, for the less severely depressed and functionally impaired patients.

Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants

2016-03-01

Ronald S. Duman , George K. Aghajanian , Gerard Sanacora +1 more

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A Comparison of Nefazodone, the Cognitive Behavioral-Analysis System of Psychotherapy, and Their Combination for the Treatment of Chronic Depression

2000-05-18

Martín Keller , James P. McCullough , Daniel N. Klein +7 more

Patients with chronic forms of major depression are difficult to treat, and the relative efficacy of medications and psychotherapy is uncertain. Patients with chronic forms of major depression are difficult to treat, and the relative efficacy of medications and psychotherapy is uncertain.

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NMDAR inhibition-independent antidepressant actions of ketamine metabolites

2016-05-03

Panos Zanos , Ruin Moaddel , Patrick J. Morris +7 more

Screening Depressed Patients in Family Practice

1972-12-01

Aaron T. Beck , Roy W. Beck

Depression assumes many masks in general medical practice. Thus, diagnosis is often difficult and may be missed. To help identify the depressed patient, the physician can use a simple 13 … Depression assumes many masks in general medical practice. Thus, diagnosis is often difficult and may be missed. To help identify the depressed patient, the physician can use a simple 13 item questionnaire that the patient can complete in about five minutes. Although the physician may have to probe further for a more precise evaluation of the level of depression, the questionnaire can indicate probable severity.

Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017

2017-09-14

Christoph Hiemke , N. Bergemann , H.‐W. Clement +7 more

Therapeutic drug monitoring (TDM) is the quantification and interpretation of drug concentrations in blood to optimize pharmacotherapy. It considers the interindividual variability of pharmacokinetics and thus enables personalized pharmacotherapy. In … Therapeutic drug monitoring (TDM) is the quantification and interpretation of drug concentrations in blood to optimize pharmacotherapy. It considers the interindividual variability of pharmacokinetics and thus enables personalized pharmacotherapy. In psychiatry and neurology, patient populations that may particularly benefit from TDM are children and adolescents, pregnant women, elderly patients, individuals with intellectual disabilities, patients with substance abuse disorders, forensic psychiatric patients or patients with known or suspected pharmacokinetic abnormalities. Non-response at therapeutic doses, uncertain drug adherence, suboptimal tolerability, or pharmacokinetic drug-drug interactions are typical indications for TDM. However, the potential benefits of TDM to optimize pharmacotherapy can only be obtained if the method is adequately integrated in the clinical treatment process. To supply treating physicians and laboratories with valid information on TDM, the TDM task force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued their first guidelines for TDM in psychiatry in 2004. After an update in 2011, it was time for the next update. Following the new guidelines holds the potential to improve neuropsychopharmacotherapy, accelerate the recovery of many patients, and reduce health care costs.

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Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis

2018-02-21

Andrea Cipriani , Toshi A. Furukawa , Georgia Salanti +7 more

Major depressive disorder is one of the most common, burdensome, and costly psychiatric disorders worldwide in adults. Pharmacological and non-pharmacological treatments are available; however, because of inadequate resources, antidepressants are … Major depressive disorder is one of the most common, burdensome, and costly psychiatric disorders worldwide in adults. Pharmacological and non-pharmacological treatments are available; however, because of inadequate resources, antidepressants are used more frequently than psychological interventions. Prescription of these agents should be informed by the best available evidence. Therefore, we aimed to update and expand our previous work to compare and rank antidepressants for the acute treatment of adults with unipolar major depressive disorder.We did a systematic review and network meta-analysis. We searched Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS database, MEDLINE, MEDLINE In-Process, PsycINFO, the websites of regulatory agencies, and international registers for published and unpublished, double-blind, randomised controlled trials from their inception to Jan 8, 2016. We included placebo-controlled and head-to-head trials of 21 antidepressants used for the acute treatment of adults (≥18 years old and of both sexes) with major depressive disorder diagnosed according to standard operationalised criteria. We excluded quasi-randomised trials and trials that were incomplete or included 20% or more of participants with bipolar disorder, psychotic depression, or treatment-resistant depression; or patients with a serious concomitant medical illness. We extracted data following a predefined hierarchy. In network meta-analysis, we used group-level data. We assessed the studies' risk of bias in accordance to the Cochrane Handbook for Systematic Reviews of Interventions, and certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. Primary outcomes were efficacy (response rate) and acceptability (treatment discontinuations due to any cause). We estimated summary odds ratios (ORs) using pairwise and network meta-analysis with random effects. This study is registered with PROSPERO, number CRD42012002291.We identified 28 552 citations and of these included 522 trials comprising 116 477 participants. In terms of efficacy, all antidepressants were more effective than placebo, with ORs ranging between 2·13 (95% credible interval [CrI] 1·89-2·41) for amitriptyline and 1·37 (1·16-1·63) for reboxetine. For acceptability, only agomelatine (OR 0·84, 95% CrI 0·72-0·97) and fluoxetine (0·88, 0·80-0·96) were associated with fewer dropouts than placebo, whereas clomipramine was worse than placebo (1·30, 1·01-1·68). When all trials were considered, differences in ORs between antidepressants ranged from 1·15 to 1·55 for efficacy and from 0·64 to 0·83 for acceptability, with wide CrIs on most of the comparative analyses. In head-to-head studies, agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine, and vortioxetine were more effective than other antidepressants (range of ORs 1·19-1·96), whereas fluoxetine, fluvoxamine, reboxetine, and trazodone were the least efficacious drugs (0·51-0·84). For acceptability, agomelatine, citalopram, escitalopram, fluoxetine, sertraline, and vortioxetine were more tolerable than other antidepressants (range of ORs 0·43-0·77), whereas amitriptyline, clomipramine, duloxetine, fluvoxamine, reboxetine, trazodone, and venlafaxine had the highest dropout rates (1·30-2·32). 46 (9%) of 522 trials were rated as high risk of bias, 380 (73%) trials as moderate, and 96 (18%) as low; and the certainty of evidence was moderate to very low.All antidepressants were more efficacious than placebo in adults with major depressive disorder. Smaller differences between active drugs were found when placebo-controlled trials were included in the analysis, whereas there was more variability in efficacy and acceptability in head-to-head trials. These results should serve evidence-based practice and inform patients, physicians, guideline developers, and policy makers on the relative merits of the different antidepressants.National Institute for Health Research Oxford Health Biomedical Research Centre and the Japan Society for the Promotion of Science.

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Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms

2018-06-26

Panos Zanos , Ruin Moaddel , Patrick J. Morris +7 more

Ketamine, a racemic mixture consisting of (<i>S</i>)- and (<i>R</i>)-ketamine, has been in clinical use since 1970. Although best characterized for its dissociative anesthetic properties, ketamine also exerts analgesic, anti-inflammatory, and … Ketamine, a racemic mixture consisting of (<i>S</i>)- and (<i>R</i>)-ketamine, has been in clinical use since 1970. Although best characterized for its dissociative anesthetic properties, ketamine also exerts analgesic, anti-inflammatory, and antidepressant actions. We provide a comprehensive review of these therapeutic uses, emphasizing drug dose, route of administration, and the time course of these effects. Dissociative, psychotomimetic, cognitive, and peripheral side effects associated with short-term or prolonged exposure, as well as recreational ketamine use, are also discussed. We further describe ketamine's pharmacokinetics, including its rapid and extensive metabolism to norketamine, dehydronorketamine, hydroxyketamine, and hydroxynorketamine (HNK) metabolites. Whereas the anesthetic and analgesic properties of ketamine are generally attributed to direct ketamine-induced inhibition of <i>N</i>-methyl-D-aspartate receptors, other putative lower-affinity pharmacological targets of ketamine include, but are not limited to, γ-amynobutyric acid (GABA), dopamine, serotonin, sigma, opioid, and cholinergic receptors, as well as voltage-gated sodium and hyperpolarization-activated cyclic nucleotide-gated channels. We examine the evidence supporting the relevance of these targets of ketamine and its metabolites to the clinical effects of the drug. Ketamine metabolites may have broader clinical relevance than was previously considered, given that HNK metabolites have antidepressant efficacy in preclinical studies. Overall, pharmacological target deconvolution of ketamine and its metabolites will provide insight critical to the development of new pharmacotherapies that possess the desirable clinical effects of ketamine, but limit undesirable side effects.

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Problems of Drug Dependence

1969-04-01

Depression

2018-11-01

Gin S. Malhi , J. John Mann

Racial-Ethnic Disparities in Ketamine and Esketamine Therapy for Major Depressive Disorder

2025-06-25

Michael Liu , Rachel Branning , Austin Lee +2 more | Psychiatric Services

This study sought to investigate racial-ethnic disparities in the utilization of intravenous ketamine and intranasal esketamine therapy for major depressive disorder. The TriNetX platform was used to identify 861,179 patients … This study sought to investigate racial-ethnic disparities in the utilization of intravenous ketamine and intranasal esketamine therapy for major depressive disorder. The TriNetX platform was used to identify 861,179 patients diagnosed as having moderate-to-severe recurrent major depressive disorder between January 2019 and October 2024. Patients were divided into non-Hispanic White, non-Hispanic Black, non-Hispanic Asian, and Hispanic cohorts. Propensity score matching (PSM) was used to match minority cohorts with White patients. Risk ratios (RRs) with 95% confidence intervals (CIs) were calculated to compare ketamine and esketamine utilization across racial-ethnic groups. After PSM, the authors found that ketamine was prescribed at lower rates among Black (RR=0.75, 95% CI=0.72-0.78), Hispanic (RR=0.71, 95% CI=0.68-0.75), and Asian (RR=0.65, 95% CI=0.57-0.75) patients compared with White patients. Esketamine was utilized at lower rates among Black patients (RR=0.74, 95% CI=0.62-0.88) and at higher rates among Hispanic patients (RR=1.45, 95% CI=1.24-1.69), whereas Asian patients showed no significant difference. Within-group comparison among Black and White patients found that individuals who received ketamine or esketamine in both cohorts had more comorbid general medical and psychiatric conditions than those who did not. Significant racial-ethnic disparities exist in the utilization of ketamine and esketamine therapies for major depressive disorder, particularly affecting Black patients. Future research should investigate the underlying causes of these disparities and develop strategies to ensure equitable access to ketamine and esketamine for all patients with major depressive disorder.

Responding to medicinal and non‐medicinal ketamine use

2025-06-24

Owen Bowden‐Jones , Arun Sahai , Paul I. Dargan | Addiction

Ketamine and Esketamine in Psychiatry: A Comparative Review Emphasizing Neuroplasticity and Clinical Applications

2025-06-23

Georgios Mikellides | Psychoactives

Ketamine and esketamine are two closely related compounds with fast-acting antidepressant properties that have reshaped the treatment landscape for individuals with treatment-resistant depression (TRD). Originally developed as anesthetic agents, both … Ketamine and esketamine are two closely related compounds with fast-acting antidepressant properties that have reshaped the treatment landscape for individuals with treatment-resistant depression (TRD). Originally developed as anesthetic agents, both have since demonstrated rapid and robust antidepressant effects in patients who have not responded to conventional treatments such as selective serotonin reuptake inhibitors (SSRIs) or cognitive behavioral therapy. This narrative review synthesizes evidence on their pharmacology, mechanisms of action, clinical efficacy, safety profiles, and regulatory considerations, with a particular focus on their neuroplastic effects. While ketamine is a racemic mixture composed of equal parts R- and S-enantiomers, esketamine consists solely of the S-enantiomer and has been approved for intranasal use by the FDA and EMA for TRD. These agents have been shown to produce symptom relief within hours of administration—an unprecedented effect in psychiatric pharmacology. This rapid onset is particularly valuable in managing suicidal ideation, offering potential lifesaving benefits in acute settings. Furthermore, ketamine and esketamine’s influence on synaptic plasticity, brain-derived neurotrophic factor (BDNF), and glutamate transmission provides insights into novel therapeutic targets beyond monoaminergic systems. This review incorporates recent real-world findings and peer-reviewed literature to contextualize the clinical use of these agents in modern psychiatry, bridging experimental research with practical application.

The Role of the 5-HTTLPR Gene Variation of the SLC6A4 Serotonergic System in the Development of Addictive Disorders: A Narrative Review

2025-06-23

A.V. Krylov , Н.И. Павлова , A.A. Bochurov | Consortium Psychiatricum

BACKGROUND: Addictive disorders remain a global problem, affecting health, society and the economy. The etiopathogenesis of addictions, which have a multifactorial nature, is poorly understood, making it difficult to develop … BACKGROUND: Addictive disorders remain a global problem, affecting health, society and the economy. The etiopathogenesis of addictions, which have a multifactorial nature, is poorly understood, making it difficult to develop personalized treatment approaches. Of particular interest is the SLC6A4 gene, which regulates serotonergic transmission. The 5-HTTLPR variation of this gene is associated with the risk of addictions, but the data are contradictory due to the heterogeneity of clinical manifestations and pleiotropic effects of the gene. Integration of genetic, environmental and neurobiological factors into multidimensional models is becoming relevant.AIM: The aim of this study is to assess the role of 5-HTTLPR variations in the SLC6A4 gene of the serotonergic system in the development of addictive disorders.METHODS: The manuscripts were searched in the MEDLINE and eLIBRARY.RU databases using the keywords in Russian and English: “SLC6A4”, “5-HTTLPR”, “addictive disorders”, “pharmacogenetics”, “serotonin”, “antidepressants”, “ethnic differences”. After eliminating duplicates and a two-stage screening (by titles/annotations and full-text analysis) of the 1,561 discovered papers, the final review included 41 publications that meet the stated inclusion criteria.RESULTS: The S-allele of 5-HTTLPR is associated with an increased risk of addictions and comorbid affective disorders, but its role is ambiguous due to the heterogeneity of symptoms. Ethnic differences have been identified: the S-allele predominates (70.6–80.9%) in Asian populations, the L-allele in Europeans (38.5–66.7%). Unique neurobiological markers for S-allele carriers have not been established, and the pleiotropic effects of SLC6A4 are also observed in other mental disorders, which reduces its specificity for addictions.CONCLUSION: The inconsistency of the data on 5-HTTLPR highlights the need to take into account ethnic specificity and develop multivariate models that integrate genetic, environmental and clinical factors. This will improve risk prediction (development of addictions), personalization of therapy and the effectiveness of pharmacogenetic approaches, reducing the likelihood of adverse reactions.

Development of the treatment prediction model in the artificial intelligence in depression – medication enhancement study

2025-06-23

David Benrimoh , Caitrin Armstrong , Joseph Mehltretter +7 more | npj Mental Health Research

We introduce an artificial intelligence model to personalize treatment in major depression, which was deployed in the Artificial Intelligence in Depression: Medication Enhancement Study. We predict probabilities of remission across … We introduce an artificial intelligence model to personalize treatment in major depression, which was deployed in the Artificial Intelligence in Depression: Medication Enhancement Study. We predict probabilities of remission across multiple pharmacological treatments, validate model predictions, and examine them for biases. Data from 9042 adults with moderate to severe major depression from antidepressant clinical trials were used to train a deep learning model. On the held-out test-set, the model demonstrated an AUC of 0.65, outperformed a null model (p = 0.01). The model increased population remission rate in hypothetical and actual improvement testing. While the model identified escitalopram as generally outperforming other drugs (consistent with the input data), there was otherwise significant variation in drug rankings. The model did not amplify potentially harmful biases. We demonstrate the first model capable of predicting outcomes for 10 treatments, intended to be used at or near the start of treatment to personalize treatment selection.

Supplemental Material for Antidepressant Medication or Short-Term Psychodynamic Psychotherapy for Depression? A Systematic Review and Meta-Analysis of Individual Participant Data

2025-06-23

| Clinical Psychology Science and Practice

Registration Open Now: Virtual Courses on Addictions and Their Treatment (Sep 12–13, 2025) and Advanced Addiction Psychopharmacology (Sep 20–21, 2025)

2025-06-22

| American Journal on Addictions

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A Comprehensive Review on Major Depressive Disorder: Exploring Etiology, Pathogenesis and Clinical Approaches

2025-06-21

Anshula Mehra , Jaswant L. Khanna , Gurpreet Singh +2 more | Current Behavioral Neuroscience Reports

A randomized, double-blind, placebo-controlled, Phase 1 study to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of an immediate-release oral ketamine capsule in healthy volunteers

2025-06-20

Mutahira M. Qureshi , Daniel Silman , Romayne Gadelrab +7 more | Journal of Psychopharmacology

Background: Ketamine, a rapid-acting N-methyl-D-aspartate receptor antagonist used as a therapeutic for treatment-resistant depression (TRD), is usually administered intravenously or intranasally. Aims: This randomized, double-blind, placebo-controlled, Phase 1 study investigated … Background: Ketamine, a rapid-acting N-methyl-D-aspartate receptor antagonist used as a therapeutic for treatment-resistant depression (TRD), is usually administered intravenously or intranasally. Aims: This randomized, double-blind, placebo-controlled, Phase 1 study investigated safety and tolerability (primary endpoint), pharmacokinetics (PK) and pharmacodynamics (PD) of an immediate-release oral ketamine. Methods: Healthy volunteers (18–55 years) were randomized to each receive two single doses of oral ketamine (40–240 mg) and one oral placebo dose. Treatment-emergent adverse events (TEAEs) and PK and PD assessments (e.g., Bond and Lader visual analogue scale, Modified Observer’s Assessment of Alertness/Sedation Scale) were assessed up to 24 h after dosing. Descriptive statistics were used. Results: Nineteen participants were randomized (mean age: 31 years; male, 68%); 18 completed the study. Eighty mild or moderate TEAEs were reported following oral ketamine (40–240 mg) and five following placebo. There were no TEAE-related discontinuations. Most TEAEs (86%) were considered probably related to study drug. The most common TEAEs with oral ketamine were dissociation (26 events), dizziness (nine events) and headache (nine events). A positive relationship between increasing ketamine doses and dissociation events was observed. PK parameters ( C max , AUC inf ) of oral ketamine and its primary metabolites (2S,6S;2R,6R-hydroxynorketamine, R/S-norketamine) were dose proportional. Transient changes in mood and dissociation were detected 1 h postdose with a return to predose values after ~4 h. Conclusions: There were no unexpected safety signals with oral ketamine. PK properties were consistent with those reported for other rapid-acting formulations. These findings warrant further investigation of oral ketamine capsules in TRD (EudraCT No. 2019-001019-22).

KETAMIR-2, a new molecular entity and novel ketamine analog

2025-06-20

Itzchak Angel , Rita Perelroizen , Wendy Deffains +3 more | Frontiers in Pharmacology

Ketamir-2 is a new molecular entity, and a novel ketamine analog designed to improve oral bioavailability, and offer a superior safety profile compared to existing ketamine treatments. It was found … Ketamir-2 is a new molecular entity, and a novel ketamine analog designed to improve oral bioavailability, and offer a superior safety profile compared to existing ketamine treatments. It was found that Ketamir-2 is a low affinity NMDA receptor antagonist, that selectively binds to the PCP site. Its IC 50 on this receptor site is ∼100 µM. Ketamine acts as an NMDA receptor antagonist (0.5–1 µM affinity) and influences opioid receptors, monoaminergic systems (such as serotonin and dopamine). The selectivity of Ketamir-2 was evaluated across a broad range of receptors, transporters, and binding sites, but no activity was detected. Ketamir-2 is a lower affinity and selective PCP-site NMDA antagonist, compared with ketamine. Upon oral administration, Ketamir-2 does not induce hyperlocomotion in mice. Thus, it is different from Ketamine, which induces marked hyperlocomotion, a behavior which is thought to mimic the psychomotor agitation and disorganized behavior seen in schizophrenia, often linked to disruptions in brain neurotransmitter systems. Ketamir-2 was also evaluated via several pharmacological tests in mice to evaluate its anti-depressive and anxiolytic effects. These tests included the Open Field test (OFT), Elevated Plus Maze (EPM), and Forced Swimming Test (FST); all of which are commonly employed behavioral assays used to evaluate the efficacy of anxiety and depression medications. While showing significant effects in these tests at variable doses, ketamine, which was used as a positive control, did not differ from vehicle treatment or showed an opposite response to Ketamir in the majority of the tests studied.

Alzheimer's Disease and Drug Addiction

2025-06-20

Joy Louise Gumikiriza‐Onoria , Dennis Buwembo , Rita Nassanga +1 more | CRC Press eBooks

Adverse Effects Associated With High-Dose Ketamine Infusions For Refractory Pain And Psychiatric Conditions

2025-06-19

Elika D Javaheri , Christopher Wie , Stephen Covington +5 more | Current Pain and Headache Reports

Drugs Acting on the Nervous System

2025-06-19

| Cambridge University Press eBooks

Moderators of antidepressant augmentation versus switch in the OPTIMUM randomised controlled trial

2025-06-19

Helena K. Kim , Jordan F. Karp , Helen Lavretsky +7 more | The British Journal of Psychiatry

Background Older adults with treatment-resistant depression (TRD) benefit more from treatment augmentation than switching. It is useful to identify moderators that influence these treatment strategies for personalised medicine. Aims Our … Background Older adults with treatment-resistant depression (TRD) benefit more from treatment augmentation than switching. It is useful to identify moderators that influence these treatment strategies for personalised medicine. Aims Our objective was to test whether age, executive dysfunction, comorbid medical burden, comorbid anxiety or the number of previous adequate antidepressant trials could moderate the superiority of augmentation over switching. A significant moderator would influence the differential effect of augmentation versus switching on treatment outcomes. Method We performed a preplanned moderation analysis of data from the Optimizing Outcomes of Treatment-Resistant Depression in Older Adults (OPTIMUM) randomised controlled trial ( N = 742). Participants were 60 years old or older with TRD. Participants were either (a) randomised to antidepressant augmentation with aripiprazole (2.5–15 mg), bupropion (150–450 mg) or lithium (target serum drug level 0.6 mmol/L) or (b) switched to bupropion (150–450 mg) or nortriptyline (target serum drug level 80–120 ng/mL). Treatment duration was 10 weeks. The two main outcomes of this analysis were (a) symptom improvement, defined as change in Montgomery–Asberg Depression Rating Scale (MADRS) scores from baseline to week 10 and (b) remission, defined as MADRS score of 10 or less at week 10. Results Of the 742 participants, 480 were randomised to augmentation and 262 to switching. The number of adequate previous antidepressant trials was a significant moderator of depression symptom improvement ( b = −1.6, t = −2.1, P = 0.033, 95% CI [−3.0, −0.1], where b is the coefficient of the relationship (i.e. effect size), and t is the t -statistic for that coefficient associated with the P -value). The effect was similar across all augmentation strategies. No other putative moderators were significant. Conclusions Augmenting was superior to switching antidepressants only in older patients with fewer than three previous antidepressant trials. This suggests that other intervention strategies should be considered following three or more trials.

Ketamine-Induced Uropathy in a High-Prevalence Region: Knowledge, Diagnostic Practices, and Treatment Patterns Among Primary and Secondary Care Providers

2025-06-19

Zakaria W Shkoukani , P G Gopi , Les Tate +3 more | Cureus

Functional connectivity alterations of the pregenual anterior cingulate cortex by ketamine and the modulation by lamotrigine

2025-06-19

David Weigner , Marvin Sören Meiering , Anne Weigand +7 more | Journal of Psychopharmacology

Background: Neuroimaging studies have linked the beneficial effects of subanaesthetic ketamine doses in psychiatric conditions characterized by chronic stress pathology (CSP) to altered functional connectivity (FC) within the pregenual anterior … Background: Neuroimaging studies have linked the beneficial effects of subanaesthetic ketamine doses in psychiatric conditions characterized by chronic stress pathology (CSP) to altered functional connectivity (FC) within the pregenual anterior cingulate cortex (pgACC). Previous research indicates a potential role of glutamate concentration in FC changes; however, the precise relationship between glutamate release and increased FC remains unclear. Lamotrigine, a glutamate-release inhibitor, allows deeper exploration of this relationship. Additionally, CSP and treatment efficacy are closely associated with alterations in working memory (WM), necessitating the examination of FC during resting state and WM tasks. Aims: This study aimed to investigate the acute and sustained effects of altered glutamate transmission induced by ketamine and lamotrigine on pgACC FC during rest and WM. Methods: In this double-blind, placebo-controlled, randomized, single-dose, parallel-group study, resting-state and task-related functional Magnetic Resonance Imaging (fMRI) data were collected at baseline, during and 24 h after ketamine administration in 75 healthy participants. Participants were randomized to receive ketamine, ketamine with lamotrigine pretreatment or placebo. FC analyses utilized pgACC masks derived from the Julich Brain Atlas. Results: Ketamine infusion significantly enhanced FC between the pgACC and dorsomedial prefrontal cortex during the WM task, and increased resting-state FC between the pgACC and left insula. These effects were absent following lamotrigine pretreatment. Conclusions: The findings support the hypothesis that ketamine’s favourable effects, reflected by enhanced FC within key neural networks, may be attributable to glutamate release.

Ketamine-induced bladder syndrome: Recognition as a key differential diagnosis and the need to curb recreational use

2025-06-19

Mohsin Malik , Harshali Kumar , K.P.W.Christopher Perera | Indian Journal of Case Reports

The recreational use of ketamine is becoming increasingly widespread, largely due to its dissociative and anesthetic properties, as well as its accessibility and affordability. A significant and often irreversible impact … The recreational use of ketamine is becoming increasingly widespread, largely due to its dissociative and anesthetic properties, as well as its accessibility and affordability. A significant and often irreversible impact on the urinary system has recently emerged as a concerning consequence of its recreational use. We present a case report of a young man who has been using ketamine recreationally for less than a year and has developed ketamine bladder syndrome. Within a few months, the patient developed acute kidney injury and some liver damage, as indicated by his blood tests, while continuing to take ketamine.

The DEPRE’5 study: pragmatic, multicentre, five-arm, parallel-group randomised controlled trial with blinded assessment to compare treatment strategies in major depression after a failed selective serotonin reuptake inhibitor treatment

2025-06-18

Víctor Pérez , Dolors Puigdemont , Javier de Diego-Adeliño +7 more | The British Journal of Psychiatry

Background Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for major depressive disorder (MDD), but initial outcomes can be modest. Aims To compare SSRI dose optimisation with four alternative … Background Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for major depressive disorder (MDD), but initial outcomes can be modest. Aims To compare SSRI dose optimisation with four alternative second-line strategies in MDD patients unresponsive to an SSRI. Method Of 257 participants, 51 were randomised to SSRI dose optimisation (SSRI-Opt), 46 to lithium augmentation (SSRI+Li), 48 to nortriptyline combination (SSRI+NTP), 55 to switch to venlafaxine (VEN) and 57 to problem-solving therapy (SSRI+PST). Primary outcomes were week-6 response/remission rates, assessed by blinded evaluators using the 17-item Hamilton Depression Rating Scale (HDRS-17). Changes in HDRS-17 scores, global improvement and safety outcomes were also explored. EudraCT No. 2007-002130-11. Results Alternative second-line strategies led to higher response (28.2% v. 14.3%, odds ratio = 2.36 [95% CI 1.0–5.6], p = 0.05) and remission (16.9% v. 12.2%, odds ratio = 1.46, [95% CI 0.57–3.71], p = 0.27) rates, with greater HDRS-17 score reductions (−2.6 [95% CI −4.9 to −0.4], p = 0.021]) than SSRI-Opt. Significant/marginally significant effects were only observed in both response rates and HDRS-17 decreases for VEN (odds ratio = 2.53 [95% CI 0.94–6.80], p = 0.067; HDRS-17 difference: −2.7 [95% CI −5.5 to 0.0], p = 0.054) and for SSRI+PST (odds ratio = 2.46 [95% CI 0.92 to 6.62], p = 0.074; HDRS-17 difference: −3.1 [95% CI −5.8 to −0.3], p = 0.032). The SSRI+PST group reported the fewest adverse effects, while SSRI+NTP experienced the most (28.1% v. 75%; p < 0.01), largely mild. Conclusions Patients with MDD and insufficient response to SSRIs would benefit from any other second-line strategy aside from dose optimisation. With limited statistical power, switching to venlafaxine and adding psychotherapy yielded the most consistent results in the DEPRE'5 study.

Long‐Term Clinical Response to Medical Treatment, Behavioral Therapy, or Their Combination in Cats With Hyperesthesia Syndrome

2025-06-17

Claudia Pauciulo , Stefania Uccheddu , Andrea Corda +4 more | Journal of Veterinary Internal Medicine

ABSTRACT Background Hyperesthesia syndrome (HS) is a common yet poorly understood condition in cats, with hypothesized neurological and behavioral causes and limited data on outcomes and treatment. Objectives This study … ABSTRACT Background Hyperesthesia syndrome (HS) is a common yet poorly understood condition in cats, with hypothesized neurological and behavioral causes and limited data on outcomes and treatment. Objectives This study aimed to describe the clinical outcomes and the treatment response of 28 cats with HS, managed through various therapeutic strategies. Animals Clinical records of 28 cats with HS and minimum of 1‐year follow‐up were reviewed. Methods Retrospective, observational, descriptive study conducted on a case series of cats affected by HS. Sixteen cats (57%) received fluoxetine alone (Fluoxetine‐only), seven (25%) were managed with behavioral modification and gabapentin or fluoxetine (Fluoxetine/Gabapentin + Behavior) and five (18%) were treated with behavioral modification alone (Behavior‐only). Results An episode‐free period (EFP) ≥ 9 months was observed in 23 (82%) cats. Fifteen cats (94%) in the Fluoxetine‐only group experienced an EFP of ≥ 9 months. Moreover, they had a shorter time to recovery (median [IQR] = 8 [3.5–18] days) compared to the Fluoxetine/Gabapentin + Behavior and Behavior‐only groups (median [IQR] = 100 [90–210] and 60 [30–90] days, respectively). At the 1‐year follow‐up, 26 (93%) cats no longer had HS clinical signs and 14 (50%) were still under pharmacotherapy. Relapses were reported only in one case (4%). Conclusions Most of the cat's diagnosed with HS, and managed through various therapeutic strategies, experienced an EFP of more than 9 months and showed absence of clinical signs at 1 year follow‐up.

Increased recreational ketamine use and subsequent outbreak of urological complications in The Netherlands

2025-06-17

Antoinette van Riel , Wouter M. H. van der Sanden , Laetitia M.O. de Kort | Clinical Toxicology

Recreational ketamine use has increased in the last decades with incidental reports of urological complications. This study aimed to explore trends in the number of acute intoxications and urological complications … Recreational ketamine use has increased in the last decades with incidental reports of urological complications. This study aimed to explore trends in the number of acute intoxications and urological complications from recreational ketamine use in the Netherlands. We retrospectively studied data from 2018 to 2024 from inquiries on ketamine toxicity to the Dutch Poisons Information Centre and data from the first outpatient clinic dedicated to ketamine-induced uropathy in the Netherlands at Jeroen Bosch Hospital, 's-Hertogenbosch. An increase was observed in the number of intoxications with ketamine reported to the poisons centre (from 33 in 2018 to 139 in 2024), in 12 cases (2.4%) urological complaints were reported. The number of patients with ketamine-induced uropathy treated by the outpatient clinic increased from zero in 2018 to 137 in 2024. Long-term and extensive ketamine use (>1 g/day for a median of 35 months, with a median amount of 18 g/week) was associated with urological complaints. Ketamine users in our study were predominantly males in their twenties. Co-exposures were common, 65.1% of acutely intoxicated patients and 72.1% of patients with uropathy reported using other drugs, including alcohol, in addition to ketamine. Fifty-one outpatients developed severe uropathy requiring surgery, ultimately leading to cystectomy and urinary deviation in three cases. This study combines data from a poisons information centre and a dedicated urological ketamine outpatient clinic and describes a large cohort of patients with ketamine-induced uropathy. The extent of complications from chronic recreational ketamine use in the Netherlands only became clear from the data of the urological outpatient clinic at Jeroen Bosch Hospital, 's-Hertogenbosch. Ketamine-induced uropathy is rising in the Netherlands. Cooperation between poisons centres and medical specialities can enhance toxicovigilance. Increased awareness among potential users and health care providers is pivotal to prevent this from developing into a public health crisis.

Antidepresivos a largo plazo: ¿tratamiento adecuado o desafío para la salud pública?

2025-06-17

Carolina Sánchez , Jordi Amat | Atención Primaria

Identifying Predictors of Serious Adverse Events in Antidepressant Treatment from a Decade-Long Nationwide Pharmacovigilance Study: Impact of Dementia and Parkinson’s Disease Treatment

2025-06-17

Jungmin Han , Minsung Kim , Yujin Kim +3 more | Medicina

Backgrounds and Objectives: This study aims to characterize the prevalence and severity of antidepressant-associated adverse drug events (ADEs) and to identify predictors strongly associated with serious adverse events (SAEs). Materials … Backgrounds and Objectives: This study aims to characterize the prevalence and severity of antidepressant-associated adverse drug events (ADEs) and to identify predictors strongly associated with serious adverse events (SAEs). Materials and Methods: Disproportionality analysis on antidepressant-related ADEs spontaneously reported to the Korea Adverse event Reporting System (KIDS KAERS DB) from 2014 to 2023 was performed. Multiple logistic regression was conducted to identify predictors associated with SAEs. Sensitivity analysis was performed to validate the overall findings and assess the robustness of associations across subgroups defined by completeness of demographic data (age and sex), elderly age-stratification, and causality assessment. The study protocol was approved by the Kyung Hee University institutional review board. Results: Among 21,103 antidepressant-related ADEs, duloxetine was the most etiologic medication, followed by amitriptyline and escitalopram. Fluoxetine is the only agent with a high likelihood of reporting SAEs. ADEs involving vascular (extracardiac) disorders (ROR 42.42, 95% CI 13.19-136.42) and liver and biliary system disorders (ROR 7.84, 95% CI 3.77-16.29) were most likely to be SAEs. The predictors associated with substantial increased SAE risk were fluoxetine use (OR 2.71, 95% CI 1.68-4.39), male sex (OR 1.48, 95% CI 1.11-1.98), and concomitant administration of antiparkinsonian treatment (OR 8.29, 95% CI 3.61-19.06) and antidementia treatment (OR 2.94, 95% CI 1.34-6.05). Sensitivity analyses demonstrated similar and consistent findings. However, reversed trends in the association between SOC-based ADEs and sex were observed in the sensitivity analysis restricted to cases with "certain" and "probable" causality. Conclusions: The type of antidepressant, concomitant medications, and sex are major predictors for SAE risk. Further controlled studies on the impact of comorbidities and polypharmacy on antidepressant-related SAEs are warranted.

Rapid treatment center for depression in China: constructive reflections and transnational implications

2025-06-16

Zhan-Ming Shi , Xingbing Huang , Yanling Zhou +4 more | Frontiers in Psychiatry

Enhancing the early diagnosis and standardized treatment of major depressive disorder (MDD), as advocated by the National Health Commission of China, is a key priority in the mental health initiatives … Enhancing the early diagnosis and standardized treatment of major depressive disorder (MDD), as advocated by the National Health Commission of China, is a key priority in the mental health initiatives of the nation. To achieve this, numerous evidence-based rapid treatment centers for MDD have been established or are currently under development across the country. These centers focus on the following primary treatment modalities for depression: electroconvulsive therapy (ECT), intravenous ketamine/esketamine, esketamine nasal spray, magnetic seizure therapy (MST), and Stanford Neuromodulation Therapy (SNT). This policy and practice review explored the application and modification of these techniques in treating depression in China, addressing their strengths and shortcomings. With particular focus on China’s rapid antidepressant treatment strategies (e.g., ECT, intravenous ketamine/esketamine, esketamine nasal spray, MST, SNT), the current policy and practice review described their potential to speed up recovery thereby providing valuable insights for other countries and regions.

Treating War Trauma with Ibogaine and 5-MEO-DMT

2025-06-16

María José Polanco , Mark D. Black | BRILL eBooks

Sex and Age Differences in Ketamine Efficacy and Safety in Chronic Pain Alleviation

2025-06-16

Gisèle Pickering , Marion Voute , Marc Sorel +2 more | Journal of Clinical Medicine

Background: Ketamine use for chronic pain and depression has increased worldwide, but sex differences in its efficacy and safety have been little studied; this study examines existing evidence to address … Background: Ketamine use for chronic pain and depression has increased worldwide, but sex differences in its efficacy and safety have been little studied; this study examines existing evidence to address this gap. Methods: A prospective, multicenter, one-year observational study in 585 chronic pain patients was performed; 256 patients had one administration of ketamine and 329 had two or more. The primary outcome looked at was mean pain intensity (0-10), assessed every month for 1 year by telephone. Secondary outcomes included measures of depression and anxiety (assessed using the Hospital Anxiety and Depression Scale), quality of life (evaluated with the 12-item Short Form Health Survey), total ketamine dosage, reported adverse effects, and concomitant treatments. Platform of Clinical Investigation, No sex or age differences were observed in ketamine efficacy in terms of pain (mean variation in women vs. men; effect size -0.5 (95% confidence interval -0.6 to -0.4) vs. -0.5 (95% confidence interval -0.7 to -0.3), p = 0.248) or the evolution of anxiety (p = 0.135) among the 585 patients. Women reported more adverse events than men (19% vs. 13%, p = 0.002). In the subgroup of 329 patients, no differences were observed in any variables, but a single ketamine administration may be more useful in men than in women (p = 0.032), especially in younger men (p = 0.045). Conclusions: Repeated ketamine administration displayed no sex or age differences in efficacy in the treatment of pain, anxiety or depression.

Intravenous ketamine to prevent post‐partum depression following cesarean under neuraxial anesthesia: A systematic review and meta‐analysis of randomized controlled trials

2025-06-14

Mohamed Aziz Daghmouri , Mohamed Ali Chaouch , Laure Ayoun +5 more | International Journal of Gynecology & Obstetrics

Vortioxetine-induced toxic hepatitis: a case report

2025-06-13

Merve Unutmaz , Fatih Kahraman , Ahmet Var | Intercontinental Journal of Emergency Medicine

A 43-year-old male patient presented to the emergency department with abdominal pain and nausea. It was learned that the patient had been taking vortioxetine 20 mg for one year due … A 43-year-old male patient presented to the emergency department with abdominal pain and nausea. It was learned that the patient had been taking vortioxetine 20 mg for one year due to depressive disorder. The patient was hospitalized in the gastroenterology service with the diagnosis of toxic hepatitis due to elevated liver enzymes in laboratory values and other etiologic factors were excluded.

For patients who are currently taking an antidepressant and are doing well, what is the likelihood of relapse after discontinuation of their medication?

2025-06-13

Faihza M. Hill , Chelsea Worstall , Tobias Rumschlag +1 more | Evidence-Based Practice

Antidepressants and old age: the risks of pharmacotherapy

2025-06-13

German V. Kukushkin , Dmitry E. Yurov , Elena V. Kalinina +2 more | Russian Medicine

The high prevalence of depression among the elderly is a significant health problem worldwide. The aging of the population only exacerbates this situation by increasing the number of patients in … The high prevalence of depression among the elderly is a significant health problem worldwide. The aging of the population only exacerbates this situation by increasing the number of patients in need of care. Along with psychotherapeutic methods of treating depression, drug therapy is widely used. However, its use in elderly patients is associated with significant difficulties due to age-related changes in the body and a high risk of adverse reactions to medications. Polymorbidity and related polypragmasia play a certain negative role, which inevitably increases the likelihood of undesirable drug interactions. In addition, changes characteristic of aging processes affect the elimination of drugs. There are various classes of antidepressants on the pharmaceutical market, the effectiveness of which is comparable. Tricyclic antidepressants (TCAS) such as amitriptyline and imipramine, due to the large number of side effects, including sedation, dry mouth, constipation and orthostatic hypotension, are not recommended for use in elderly patients. Selective serotonin reuptake inhibitors (SSRIs), for example, fluoxetine, sertraline and citalopram, have a more favorable safety profile and are the drugs of choice in the treatment of depression in the elderly and senile, although they are not without disadvantages. Selective norepinephrine and serotonin reuptake inhibitors (SSRIs), such as venlafaxine and duloxetine, have an effect on two neurotransmitters, which may increase the likelihood of side effects. Atypical antidepressants (mirtazapine, trazodone, vortioxetine and agomelatin) are a heterogeneous class of drugs that differ in their mechanism of action and safety profile. Thus, in the treatment of elderly patients, a rational choice of an antidepressant should take into account its side effects, interaction with other drugs, as well as the presence of concomitant diseases and the cost of treatment.

What if STAR*D Had Been Placebo-Controlled? A Critical Reexamination of a Foundational Study in Depression Treatment

2025-06-13

Kevin P. Kennedy , Jonathan P. Heldt , David W. Oslin | Journal of Clinical Psychopharmacology

Background: The STAR*D trial’s sequence of dose escalation, switching, and augmentation strategies has served as a model for most depression treatment guidelines. However, STAR*D was an open-label pragmatic trial that … Background: The STAR*D trial’s sequence of dose escalation, switching, and augmentation strategies has served as a model for most depression treatment guidelines. However, STAR*D was an open-label pragmatic trial that did not use a placebo control, which complicates the assessment of its outcomes. Most STAR*D treatment steps have now been studied in blinded placebo-controlled randomized trials, which could validate STAR*D and support the growing use of pragmatic trials in depression. Methods: This review evaluates outcomes from randomized controlled trials (RCTs) for the major STAR*D treatment steps: dose increase after inadequate response to an antidepressant (Level 1), switching the antidepressant after treatment nonresponse (Levels 2 and 3), augmenting an antidepressant with bupropion or buspirone (Level 2), augmenting an antidepressant with lithium or T3 thyroid hormone (Level 3), and using combination mirtazapine-venlafaxine (Level 4). Findings: RCTs have generally not replicated the findings of STAR*D. Of the major treatment steps, there is only positive evidence for lithium augmentation and α2-antagonist-serotonin-reuptake inhibitor combination. Limitations of this review include variation in the quality and quantity of comparable RCTs for each treatment level and differences in the inclusion criteria of RCTs and STAR*D. Conclusions: These findings raise questions about the evidence supporting widely used treatment strategies following an inadequate response to an initial antidepressant. They suggest that pragmatic trials should be interpreted cautiously in the absence of blinded placebo-controlled studies and point to the need for high-quality blinded clinical trials of second-step and third-step depression treatments.

Precision medicine in psychiatry: Case series on pharmacogenomic solutions for treatment-resistant depression

2025-06-13

Gryan Garcia , Christy Cotner , Robert Spano | Journal of the American Association of Nurse Practitioners

ABSTRACT Treatment-resistant depression (TRD) is a persistent challenge in psychiatry, affecting approximately 30% of patients with major depressive disorder. Defined by the failure to achieve remission after two adequate trials … ABSTRACT Treatment-resistant depression (TRD) is a persistent challenge in psychiatry, affecting approximately 30% of patients with major depressive disorder. Defined by the failure to achieve remission after two adequate trials of antidepressants at therapeutic doses, TRD significantly impairs quality of life, heightens suicide risk, and increases health care utilization and economic burden. Current treatment paradigms rely heavily on trial and error, often leading to delayed symptom relief and exposure to unnecessary side effects. This underscores the urgent need for personalized approaches to care. Pharmacogenomic testing has emerged as a transformative tool in addressing the complexities of TRD. By analyzing genetic polymorphisms, such as those in cytochrome P450 enzymes, serotonin transporter, and methylenetetrahydrofolate reductase, pharmacogenomics offers insights into drug metabolism, receptor sensitivity, and neurotransmitter synthesis. This precision approach enables clinicians to optimize antidepressant selection, dosing, and augmentation strategies, minimizing adverse effects and enhancing therapeutic outcomes. This case series highlights the clinical utility of pharmacogenomic testing in managing TRD. Three diverse cases illustrate how genetic insights guided tailored interventions, leading to significant improvements in depressive symptoms, enhanced adherence, and overall patient satisfaction. The findings underscore pharmacogenomics' potential to shift psychiatry from trial and error to precision medicine, improving outcomes for patients with complex treatment histories. Despite challenges, such as cost, accessibility, and the need for clinician training, integrating pharmacogenomics into routine practice represents a promising avenue for advancing the management of TRD and enhancing the quality of psychiatric care.

Simple and Sensitive Spectrophotometric Methods for Estimation of Vortioxetine HBr in Pharmaceutical Formulations

2025-06-12

Ayman A. Gouda , Ragaa elsheikh , Noha E.M. Elsaify +5 more | Bulletin of Faculty of Science Zagazig University

Corrigendum to Canadian Network for Mood and Anxiety Treatments (CANMAT) 2023 Update on Clinical Guidelines for Management of Major Depressive Disorder in Adults: Réseau canadien pour les traitements de l'humeur et de l'anxiété (CANMAT) 2023: Mise à jour des lignes directrices cliniques pour la prise en charge du trouble dépressif majeur chez les adultes

2025-06-09

| The Canadian Journal of Psychiatry

In vivo serotonin 1A receptor distribution in treatment-resistant depression

2025-06-03

Matej Murgaš , Christian Milz , Peter Stöhrmann +7 more | Translational Psychiatry