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Toward specific ways to combine ketamine and psychotherapy in treating depression



In major depression, remission rate in response to monoaminergic antidepressant is around 50%. The lack of strong synergies between classical antidepressants and psychotherapy may be due to the molecular effects of classical antidepressants. They modulate synapses but they do not substantially influence synaptogenesis. They also increase brain-derived neurotrophic factor (BDNF). However, for activity-dependent plasticity, BDNF release has to work in concert with activation of synaptogenesis. There has been considerable excitement about ketamine’s antidepressant effect. Ketamine leads to fast changes in synaptic function and plasticity that go well beyond effects of classical antidepressants. As a result, ketamine may turn out to have the capacity to considerably enhance the effects of psychotherapy. Such enhancing effects may become an important clinical indication for ketamine since its purely pharmacological effect is transient. This editorial outlines some mechanistic hypotheses, how Behavioral Activation, Trauma-Focused Psychotherapies and Humanistic Psychotherapy may specifically prolong ketamine’s antidepressant effects.
To be submitted as an Editorial to CNS Spectrums
Toward Specific Ways to Combine Ketamine and Psychotherapy in Treating Depression
Running title: Ketamine and Psychotherapy
Gregor Hasler, M.D.1
1Unit of Psychiatry Research, University of Fribourg, Chemin du Cardinal-Journet 3, 1752 Villars-
sur-Glâne, Fribourg, Switzerland
Gregor Hasler, M.D.
Professor and Chair
Head, Psychiatry Research Unit
University of Fribourg
Chemin du Cardinal-Journet 3
1752 Villars-sur-Glâne
In major depression, remission rate in response to monoaminergic antidepressant is around
50%. The lack of strong synergies between classical antidepressants and psychotherapy may be
due to the molecular effects of classical antidepressants. They modulate synapses but they do
not substantially influence synaptogenesis. They also increase brain-derived neurotrophic factor
(BDNF). However, for activity-dependent plasticity, BDNF release has to work in concert with
activation of synaptogenesis. There has been considerable excitement about ketamine’s
antidepressant effect. Ketamine leads to fast changes in synaptic function and plasticity that go
well beyond effects of classical antidepressants. As a result, ketamine may turn out to have the
capacity to considerably enhance the effects of psychotherapy. Such enhancing effects may
become an important clinical indication for ketamine since its purely pharmacological effect is
transient. In this editorial, I outline some mechanistic hypotheses how Behavioral Activation,
Trauma-Focused Psychotherapies and Humanistic Psychotherapy may specifically prolong
ketamine’s antidepressant effects.
Major Depressive Disorder (MDD) and depressive episodes in the course of Bipolar Disorders
(BD) are a major public health concern. In MDD, the remission rate in response to classical,
monoaminergic antidepressants is 40-60% in clinical trials, and 20-40% in naturalistic settings.
Numbers are even lower for bipolar depression. The persistence of depressive symptoms in
MDD and BD have been associated with increased risk of relapse, social and occupational
impairments, cognitive deficits and increased suicide risk.
The benefits of combining psychotherapy with classical antidepressants is a matter of debate.
Meta-analyses have consistently found small benefits from combination treatment over
treatment with an antidepressant or psychotherapy alone. However, it remains unclear whether
these benefits are clinically relevant 1,2.
All types of psychotherapies involve learning and behavioral change. One likely source of
synergies between pharmacotherapy and psychotherapy is the neuroplasticity-enhancing effect
of psychotropics that enables lasting cognitive restructuring and behavioral change. The lack of
strong synergies between classical antidepressants and psychotherapy in MDD may be due to
the molecular effects of classical antidepressant drugs on neuroplasticity. These drugs modulate
synapses but they do not substantially influence synaptogenesis. They also increase brain-
derived neurotrophic factor (BDNF). However, for activity-dependent formation and plasticity,
BDNF release has to work in concert with activation of synaptogenesis 3.
There has been considerable excitement about the discovery of ketamine’s antidepressant
effect when given at a sub-anesthetic dose. Ketamine has a clearly different therapeutic
mechanism than classical antidepressants, which is of clinical importance. For example, the
onset of action is more rapid, it effectively reduces suicidal risk, and it is effective in patients
who frequently do not respond to monoaminergic antidepressants, for example patients with
bipolar depression and depressed patients who also suffer from obesity.
Ketamine is an antagonist at the N-methyl-D-aspartate (NMDA) receptor. However, the
therapeutic mechanisms are way more complex than this receptor blockade. Particularly,
ketamine leads to fast changes in synaptic function and plasticity that go well beyond effects on
neuroplasticity of classical antidepressant compounds. Ketamine increases mTORC1 signaling,
synaptic number and function. These changes persist over a week and even longer and correlate
with the mitigation of depressive symptoms 3.
As a result, ketamine may turn out to have the capacity to considerably enhance the effects of
psychotherapy in treatment-resistant unipolar and bipolar depression. In fact, such an
enhancing effect has the potential to become an important clinical indication for ketamine. The
transient nature of ketamine’s antidepressant effects and the potentially severe side effects of a
long-term treatment with repeated applications has raised concerns about the use of this new
antidepressant in clinical settings. As a result, the identification of strategies to enhance the
sustainability of ketamine’s initial strong antidepressant effect has become an important
research question in the field 4.
There is preliminary evidence that cognitive behavioral therapy (CBT) extends the duration of
ketamine’s antidepressant effects 5.
Ketamine alters activity in brain circuits related to reward and motivation 5. In a clinical study on
MDD and BD, patients with at least moderate anhedonia at baseline were found to be 55%
more likely to respond to IV ketamine 6. Moreover, Ketamine’s pronounced pro-hedonic effects
have been associated with ketamine’s anti-suicidal effects 7. These findings are interesting in the
context of behavioral models of depression that emphasize low positive reinforcement as a
causal factor of depressed states.
The main goal of Behavioral Activation, a highly effective form of psychotherapy for depression,
is to increase environmental reinforcement. Subjective experience of environmental reward,
rather than objective reward, mediates the relationship between avoidance and mitigation of
depression. As a consequence, this approach works only if the human reward pathways are
responsive and plastic. Therefore, in MDD and BP with pronounced anhedonia, the combination
of ketamine and Behavioral Activation appears to be a highly promising approach. The
behavioral change resulting from such a combination therapy may last much longer than
ketamine’s transient antidepressant effects.
Several studies have demonstrated that inflammation is a predictor of poor response to CBT 8.
Unspecific effects such as cognitive deficits related to memory, attention, learning and fatigue
may underlie this relationship. In addition, inflammation has specific effects on social cognition
and behaviors, such as feelings of social disconnection, impaired social cognitive processing and
increased rejection sensitivity. These symptoms may have had an evolutionary survival function.
However, in modern times, they can reduce the effectiveness of psychosocial interventions,
particularly of interpersonal psychotherapies. Thus, ketamine has the potential to enhance the
effects of interpersonal and psychodynamic therapies by its anti-inflammatory effects.
Attentional and mnemonic biases toward negative information and emotions is one of the most
consistent neuropsychological findings in MDD that may even play a causal role in the
development of depressive disorders 9. In our own, unpublished data we found that ketamine
reduced pessimism, which is consistent with the finding that ketamine blocks lateral habenula
bursting 10. The combination of ketamine with Cognitive Bias Modification Therapy may prolong
ketamine’s positive neuropsychological effect.
Unfortunately, we don’t yet know the full amount of possibly diverse effects of low-dose
ketamine, as administered in MDD and BP, on cognition. However, there is consistent preclinical
evidence that ketamine has a complex effect on memory, including disruption of fear memory
consolidation and strengthening the formation of extinction memory 11. These data suggests
that ketamine may have the potential to enhance exposure-based therapies in traumatized
depressed patients and those with phobias.
Regarding neuro-plastic effects, there may be important similarities between ketamine and
other putative antidepressants that increase glutamate release, including serotonergic
hallucinogens such as LSD and psilocybin 5. At the clinical level, serotonergic hallucinogens have
the potential to induce long-term changes in certain personality traits. In particular, there is
preliminary evidence that psilocybin increased the Big-Five personality trait Openness. This
therapeutic change lasted over one year 12. Carl Rogers, the highly influential founder of
Humanistic Psychotherapy, considered openness as a core feature of therapeutic change and
the fully functionally patient: “He is able to experience all of his feelings, and is afraid of none of
his feelings. He is his own sifter of evidence, but he is open to evidence from all
sources…because of the awareness of himself which flows freely in and through his experience,
he is a fully functioning person” 13. If ketamine has similar effects on openness as hallucinogens,
it may have the potential to become an important enhancer of Humanistic Psychotherapies that
are popular among therapists and patients in naturalistic settings.
Recently, we demonstrated that ketamine can change body feelings and induce subjective
lightness and floating 14, which suggests a link between ketamine, body therapy and
mindfulness-based psychotherapies.
Depression is frequently associated with social anhedonia, increased rejection sensitivity,
impaired social communication and lack of empathy 15. In our clinical experience, ketamine
rapidly improved social functioning in depressed patients. As a consequence, it facilitated to
build up a therapeutic relationship, which is the basis of almost all psychotherapies.
In sum, the transient nature of ketamine’s antidepressant effects in concert with growing
evidence on its neuroplasticity-related therapeutic mechanisms encourage studies on
psychosocial interventions to prolong its efficacy. Table 1 summarizes the related hypotheses
described in this editorial. Research on ketamine’s effect on cognition will base such efforts on
empirically driven hypotheses.
1. Craighead WE, Dunlop BW. Combination psychotherapy and antidepressant medication
treatment for depression: for whom, when, and how. Annu Rev Psychol. 2014;65:267-300.
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psychotherapy and pharmacotherapy in the treatment of depression: a meta-analysis. Depress
Anxiety. 2009;26(3):279-288.
3. Duman RS, Aghajanian GK, Sanacora G, Krystal JH. Synaptic plasticity and depression: new
insights from stress and rapid-acting antidepressants. Nat Med. 2016;22(3):238-249.
4. Costi S, Soleimani L, Glasgow A, et al. Lithium continuation therapy following ketamine in
patients with treatment resistant unipolar depression: a randomized controlled trial.
Neuropsychopharmacology. 2019.
5. Krystal JH, Abdallah CG, Sanacora G, Charney DS, Duman RS. Ketamine: A Paradigm Shift for
Depression Research and Treatment. Neuron. 2019;101(5):774-778.
6. Thomas RK, Baker G, Lind J, Dursun S. Rapid effectiveness of intravenous ketamine for
ultraresistant depression in a clinical setting and evidence for baseline anhedonia and bipolarity
as clinical predictors of effectiveness. J Psychopharmacol. 2018;32(10):1110-1117.
7. Ballard ED, Wills K, Lally N, et al. Anhedonia as a clinical correlate of suicidal thoughts in clinical
ketamine trials. J Affect Disord. 2017;218:195-200.
8. Lopresti AL. Cognitive behaviour therapy and inflammation: A systematic review of its
relationship and the potential implications for the treatment of depression. Aust N Z J Psychiatry.
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Neuropsychopharmacology. 2004;29(10):1765-1781.
10. Yang Y, Cui Y, Sang K, et al. Ketamine blocks bursting in the lateral habenula to rapidly relieve
depression. Nature. 2018;554(7692):317-322.
11. Fattore L, Piva A, Zanda MT, Fumagalli G, Chiamulera C. Psychedelics and reconsolidation of
traumatic and appetitive maladaptive memories: focus on cannabinoids and ketamine.
Psychopharmacology (Berl). 2018;235(2):433-445.
12. MacLean KA, Johnson MW, Griffiths RR. Mystical experiences occasioned by the hallucinogen
psilocybin lead to increases in the personality domain of openness. J Psychopharmacol.
13. Rogers CR. The concept of the fully functioning person. Psychotherapy: Theory, Research &
Practice. 1963;1(1):17-26.
14. Stocker K, Hasler G, Hartmann M. The Altered-State-of-Consciousness Aspect of a Feeling of
Lightness Is Reported to Be Associated with Antidepressant Benefits by Depressed Individuals
Receiving Ketamine Infusions: A Systematic Analysis of Internet Video Testimonials. Psychother
Psychosom. 2019:1-2.
15. Kupferberg A, Bicks L, Hasler G. Social functioning in major depressive disorder. Neurosci
Biobehav Rev. 2016;69:313-332.
Table 1: Hypotheses on specific ways to combine ketamine and psychotherapy
neurobiological effect
Ketamine’s clinical
psychological effect
Combination with
Neuroplasticity in human
reward pathways !
Behavioral Activation
Social avoidance¯
Rejection sensitivity¯
Therapeutic bond!
Psychotherapy etc.
Lateral habenula
Pessimistic thinking¯
Bias toward negative
Cognitive Bias
Effects on hippocampus
and prefrontal cortex
Specific cognitive
Disruption of fear
Neuroplasticity in
thalamocortical circuits!
Personality dimension
... One leading theory of psychedelics' lasting effects categorizes them as "psychoplastogens" which rapidly stimulate a period of enhanced neuroplasticity, as well as enduring neuroplastic changes [14,15]. Neuroplasticity denotes the nervous system's ability to reorganize its structure and function and adapt to its dynamic environment [16]. ...
... Finally, the psychedelic experience itself is not the only important experience in psychedelic therapy. Enhanced neuroplasticity may also make people more responsive to other therapeutic interventions, including psychotherapy, but potentially also neurorehabilitation after stroke or brain injury [14]. Therapeutic interventions combined with antidepressants, which also modestly promote neuroplasticity, have been shown to be more effective than either intervention alone, and the same is likely true of psychedelics [164,165]. ...
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Classic psychedelics, such as LSD, psilocybin, and the DMT-containing beverage ayahuasca, show some potential to treat depression, anxiety, and addiction. Importantly, clinical improvements can last for months or years after treatment. It has been theorized that these long-term improvements arise because psychedelics rapidly and lastingly stimulate neuroplasticity. The focus of this review is on answering specific questions about the effects of psychedelics on neuroplasticity. Firstly, we review the evidence that psychedelics promote neuroplasticity and examine the cellular and molecular mechanisms behind the effects of different psychedelics on different aspects of neuroplasticity, including dendritogenesis, synaptogenesis, neurogenesis, and expression of plasticity-related genes (e.g., brain-derived neurotrophic factor and immediate early genes). We then examine where in the brain psychedelics promote neuroplasticity, particularly discussing the prefrontal cortex and hippocampus. We also examine what doses are required to produce this effect (e.g., hallucinogenic doses vs. “microdoses”), and how long purported changes in neuroplasticity last. Finally, we discuss the likely consequences of psychedelics’ effects on neuroplasticity for both patients and healthy people, and we identify important research questions that would further scientific understanding of psychedelics’ effects on neuroplasticity and its potential clinical applications.
... Importantly, this sensitivity to interpersonal conflict and anxiety around social situations can interfere with the therapeutic bond and, thus, the outcomes of therapy. Ketamine has been reported to increase the social functioning of patients with depression, reducing rejection sensitivity, social avoidance, pessimistic thinking and a bias towards negative information, which facilitates a therapeutic bond [160]. ...
... Whilst the antidepressant effects of ketamine are transient, there is emerging evidence that psychotherapies (such as CBT) can extend the duration of antidepressant effects [190]. Additionally, the experiential components of ketamine may facilitate the therapeutic bond between patient and clinician [160], which is known to be a predictor of response to treatments [191]. ...
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Anorexia nervosa (AN) is a highly complex disorder to treat, especially in severe and en‐ during cases. Whilst the precise aetiology of the disorder is uncertain, malnutrition and weight loss can contribute to reductions in grey and white matter of the brain, impairments in neuroplasticity and neurogenesis and difficulties with cognitive flexibility, memory and learning. Depression is highly comorbid in AN and may be a barrier to recovery. However, traditional antidepressants are often ineffective in alleviating depressive symptoms in underweight patients with AN. There is an urgent need for new treatment approaches for AN. This review gives a conceptual overview for the treatment of AN with ketamine. Ketamine has rapid antidepressant effects, which are hypothesised to occur via increases in glutamate, with sequelae including increased neuroplasticity, neurogenesis and synaptogenesis. This article provides an overview of the use of ketamine for common psychiatric comorbidities of AN and discusses particular safety concerns and side effects. Potential avenues for future research and specific methodological considerations are explored. Overall, there appears to be ample theoretical background, via several potential mechanisms, that warrant the exploration of ketamine as a treatment for adults with AN.
... However, there is growing evidence of prolonging the antidepressant and anxiolytic effects with the combination of ketamine treatment and psychotherapy, hereafter called ketamine-assisted psychotherapy (KAP) (Dore et al. 2019). Ketamine leads to changes in synaptic function and neuroplasticity, thus having the potential to enhance psychotherapy effects (Hasler 2020). KAP can refer to the administration of ketamine as a therapy aid by administering ketamine at low doses prior to a psychotherapy session to decrease fear and resistance to the exploration of psychological material, which is typically termed as a psycholytic experience (Dore et al. 2019). ...
This study reports on 10 frontline healthcare workers, employed during the COVID-19 pandemic and experiencing symptoms of burnout and PTSD, treated with group ketamine-assisted psychotherapy (KAP) in a private outpatient clinic setting. Participants attended 6 sessions once weekly. These included 1 preparation session, 3 ketamine sessions (2 sublingual, 1 intramuscular), 2 integration sessions. Measures of PTSD (PCL-5), depression (PHQ-9), and anxiety (GAD-7) were administered at baseline and post-treatment. During ketamine sessions, the Emotional Breakthrough Inventory (EBI) and the 30-item Mystical Experience Questionnaire (MEQ-30) were recorded. Participant feedback was gathered 1-month post-treatment. We observed improvements in participants' average PCL-5 (59% reduction), PHQ-9 (58% reduction), and GAD-7 (36% reduction) scores from pre- to post-treatment. At post-treatment, 100% of participants screened negative for PTSD, 90% had minimal/mild depression or clinically significant improvement, and 60% had minimal/mild anxiety or clinically significant improvement. MEQ and EBI scores had large variations among participants at each ketamine session. Ketamine was well tolerated, and no significant adverse events were reported. Participant feedback corroborated findings of improvements observed in mental health symptoms. We found immediate improvements treating 10 frontline healthcare workers experiencing burnout, PTSD, depression, and anxiety using weekly group KAP and integration.
... As a prototypical psychoplastogen, ketamine has been shown to rapidly promote structural and functional neuroplasticity, which may enhance (or be enhanced by) the effects of psychotherapy to maximize treatment outcomes (Joneborg et al., 2022;Olson, 2018). The formation of new neural connections, restructuring of thought patterns, and promotion of emotional learning are potential mechanisms of behavior change within this context (Drozdz et al., 2022;Hasler, 2020). Additionally, ketamine may enhance treatment adherence and patient engagement, carrying high capacity as a psychotherapeutic adjunct (Drozdz et al., 2022). ...
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Background and Aims Ketamine and esketamine have garnered interest in both psychiatric research and clinical practice for treatment-resistant depression (TRD). In this review, we examined registered trials investigating the therapeutic use of ketamine or esketamine for TRD, with the aim of characterizing emerging trends and knowledge gaps. Methods The electronic registry and results database was queried from inception to February 5, 2022, adhering to elements of the PRISMA guideline, we evaluated trial eligibility in the qualitative synthesis. Data regarding study design, drug regimens, and measures were subsequently abstracted and descriptively analyzed. Results The search returned 86 records, of which 56 trials were included in the final review. The number of trials investigating ketamine and esketamine for TRD increased since 2008, with higher peaks observed in 2015 ( n = 9) and 2021 ( n = 9). Most trials were Phase 2 (13, 23.2%) or Phase 3 (11, 19.6%), gathering preliminary data on efficacy and/or further data on safety and efficacy with variant dosing and pharmacological approaches. By and large, trials examined ketamine and esketamine as individual versus combination treatments (45% and 25%, respectively). The Montgomery-Asberg Depression Rating Scale (MADRS) was most commonly used to assess clinical outcomes (75%). Conclusions There are increasingly large-scale and late-phase trials of esketamine over ketamine for TRD, coupled with efforts to centralize evidence on these medications. Yet several trials do not assess patient characteristics that may affect treatment response, such as age, sex, and race. By understanding these design limitations, scientists and clinicians can avoid research waste and funding bodies can judiciously direct support towards high priority research.
... The dissociative effects of ketamine appear to be dose-dependent and are commonly described as having an extracorporeal sensation that can be accompanied by synesthetic hallucinations, even when given at a subanesthetic doses [1,9]. While ketamine's psychopharmacological effects on depression are rapid-acting and transient, there is a growing interest in the possibility of prolonging the antidepressant effects by combining ketamine with psychotherapy (i.e., ketamine-assisted psychotherapy, KAP) [4,10,11]. Ketamine's NMDA receptor antagonism also induces neuroplasticity, facilitating the formation of new neural connections and restructuring of thought patterns, making ketamine a potentially powerful substance as an adjunct to psychotherapy [12,13]. ...
Full-text available
Background Depression and anxiety outcome measures, safety/tolerability, patient satisfaction, and ease of implementation of group-based ketamine-assisted psychotherapy (G-KAP) delivered to patients in intensive residential eating disorder (ED) treatment were assessed. Case presentation This study reports on five participants with a diagnosis of an ED and comorbid mood and anxiety disorders who received weekly intramuscular ketamine injections in a group setting over 4 weeks. Measures of anxiety (GAD-7) and depression (PHQ-9) were administered pre-dose, 4-h post-dose, and 24-h post dose. Four of the 5 participants experienced clinically significant improvements on the PHQ-9 score (i.e., change greater than 5) while 2 of the 5 participants experienced clinically significant improvements on the GAD-7 score (i.e., change greater than 4) from pre-dose to 24-h post-dose after the last ketamine session. Dosing sessions were well tolerated, and no serious adverse events were reported. Clinical observations and participant reports corroborated improvements in depression and anxiety symptoms, good tolerability of ketamine treatment, and practical implementation of the G-KAP protocol in a residential ED treatment center. Conclusions This study suggests the potential utility of G-KAP as an adjunct to intensive, specialized ED treatment. Overall, this novel, cross-diagnostic intervention warrants future research to further explore its appropriateness in a treatment setting.
... Other recent and contrasting approaches have tended to use behavioral therapies largely outside of the period of acute drug effects (Rodriguez et al., 2016;Adams et al., 2017;Wilkinson et al., 2017Wilkinson et al., , 2021Dakwar et al., 2019Dakwar et al., , 2020Ocker et al., 2020;Shiroma et al., 2020;Azhari et al., 2021;Philipp-Muller et al., 2021;Grabski et al., 2022). This strategy presumes that, beyond the period of its immediate psychoactive function, ketamine produces a window of enhanced neuroplasticity and other neural adaptations that facilitate cognitive and behavioral interventions (Dakwar and Nunes, 2016;Wilkinson et al., 2019;Hasler, 2020). Theoretically, drug-facilitated psychotherapy could be optimized when delivered during "critical periods" of neural development, marked by exquisite sensitivity to environmental input and potentially conducive to learning (Lepow et al., 2021). ...
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Ketamine is a dissociative drug that has been used medically since the 1970s primarily as an anesthetic agent but also for various psychiatric applications. Anecdotal reports and clinical research suggest substantial potential for ketamine as a treatment in conjunction with psychological interventions. Here, we review historical and modern approaches to the use of ketamine with psychotherapy, discuss the clinical relevance of ketamine's acute psychoactive effects, propose a unique model for using esketamine (one isomeric form of ketamine) with Acceptance and Commitment Therapy (ACT), and suggest considerations for moving medication-assisted psychotherapy forward as a field.
... The authors postulated that ketamine and psychotherapy act synergistically, with therapy augmenting the response to treatment and repeated sessions accounting for the durability of effect. Furthermore, the "emergence phenomena" of ketamine [162], characterized by euphoria, lucid dreams, and hallucinations, may facilitate therapeutic rapport, patient-provider bonding, and ultimately behavior change [163,164]. While treatment courses should permit flexible dosing and individualization, KAP generally follows a three-step model, consisting of preparatory psychotherapy (step 1), ketamine dosing (step 2), and integration psychotherapy (step 3). ...
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Eating disorders (EDs) are serious, life-threatening psychiatric conditions associated with physical and psychosocial impairment, as well as high morbidity and mortality. Given the chronic refractory nature of EDs and the paucity of evidence-based treatments, there is a pressing need to identify novel approaches for this population. The noncompetitive N-methyl-D-aspartate receptor (NMDAr) antagonist, ketamine, has recently been approved for treatment-resistant depression, exerting rapid and robust antidepressant effects. It is now being investigated for several new indications, including obsessive–compulsive, post-traumatic, and substance use disorder, and shows transdiagnostic potential for EDs, particularly among clinical nonresponders. Hence, the aim of this review is to examine contemporary findings on the treatment of EDs with ketamine, whether used as a primary, adjunctive, or combination psychopharmacotherapy. Avenues for future research are also discussed. Overall, results are encouraging and point to therapeutic value; however, are limited to case series and reports on anorexia nervosa. Further empirical research is thus needed to explore ketamine efficacy across ED subgroups, establish safety profiles and optimize dosing, and develop theory-driven, targeted treatment strategies at the individual patient level.
... In addition, ketamine is hypothesized to block NMDAR on GABA interneurons, releasing the inhibition of glutamate release (109). This activates AMPAR on glutamatergic cells and subsequently increases BDNF and glutamate in the cortex (110). Ketamine and psychedelics activate cortical AMPAR and subsequently stimulate BDNF and synaptic efficacy (111). ...
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Clinical studies suggest the therapeutic potential of psychedelics, including ayahuasca, DMT, psilocybin, and LSD, in stress-related disorders. These substances induce cognitive, antidepressant, anxiolytic, and antiaddictive effects suggested to arise from biological changes similar to conventional antidepressants or the rapid-acting substance ketamine. The proposed route is by inducing brain neuroplasticity. This review attempts to summarize the evidence that psychedelics induce neuroplasticity by focusing on psychedelics' cellular and molecular neuroplasticity effects after single and repeated administration. When behavioral parameters are encountered in the selected studies, the biological pathways will be linked to the behavioral effects. Additionally, knowledge gaps in the underlying biology of clinical outcomes of psychedelics are highlighted. The literature searched yielded 344 results. Title and abstract screening reduced the sample to 35; eight were included from other sources, and full-text screening resulted in the final selection of 16 preclinical and four clinical studies. Studies ( n = 20) show that a single administration of a psychedelic produces rapid changes in plasticity mechanisms on a molecular, neuronal, synaptic, and dendritic level. The expression of plasticity-related genes and proteins, including Brain-Derived Neurotrophic Factor (BDNF), is changed after a single administration of psychedelics, resulting in changed neuroplasticity. The latter included more dendritic complexity, which outlasted the acute effects of the psychedelic. Repeated administration of a psychedelic directly stimulated neurogenesis and increased BDNF mRNA levels up to a month after treatment. Findings from the current review demonstrate that psychedelics induce molecular and cellular adaptations related to neuroplasticity and suggest those run parallel to the clinical effects of psychedelics, potentially underlying them. Future (pre)clinical research might focus on deciphering the specific cellular mechanism activated by different psychedelics and related to long-term clinical and biological effects to increase our understanding of the therapeutic potential of these compounds.
Long established as the preeminent source in its field, the eagerly anticipated fifth edition of Dr Stahl's essential textbook of psychopharmacology is here! With its use of icons and figures that form Dr Stahl's unique 'visual language', the book is the single most readable source of information on disease and drug mechanisms for all students and mental health professionals seeking to understand and utilize current therapeutics, and to anticipate the future for novel medications. Every aspect of the book has been updated, with the clarity of explanation that only Dr Stahl can bring. The new edition includes over 500 new or refreshed figures, an intuitive color scheme, fourteen new uses for older drugs and eighteen brand new drugs, coverage of Parkinson's Disease Psychosis, behavioural symptoms of dementia, and mixed features in major depressive episodes, and expanded information on the medical uses of cannabis and hallucinogen assisted psychotherapy.
The eagerly anticipated fifth edition of Dr Stahl's essential textbook of psychopharmacology is here! Using Dr Stahl's unique 'visual language', the book is the single most readable source of information on disease and drug mechanisms for all students and mental health professionals seeking to understand and utilize current therapeutics, and to anticipate the future for novel medications. The new edition includes over 500 new or refreshed figures, an intuitive color scheme, 14 new uses for older drugs and 18 brand new drugs, coverage of Parkinson's Disease Psychosis, behavioural symptoms of dementia, and mixed features in major depressive episodes, and expanded information on the medical uses of cannabis and hallucinogen assisted psychotherapy. This product combines the fifth edition of the textbook with a one-year subscription to, providing access to the full range of Dr Stahl's content. The one-year subscription is activated via a code provided with the printed book.
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Ketamine is the first exemplar of a rapid-acting antidepressant with efficacy for treatment-resistant symptoms of mood disorders. Its discovery emerged from a reconceptualization of the biology of depression. Neurobiological insights into ketamine efficacy shed new light on the mechanisms underlying antidepressant efficacy.
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Background: Intravenous ketamine has been established as an efficacious and safe treatment, with transient effect, for treatment-resistant depression. However, the effectiveness of intravenous ketamine in non-research settings and with ultraresistant depression patients remains understudied. Aims: This study aims to measure the response and remission rates in ultraresistant depression patients in a clinical setting by means of a retrospective, open label, database study. Secondarily, the study will attempt to support previous findings of clinical predictors of effectiveness with intravenous ketamine treatment. Methods: Fifty patients with ultraresistant depression were treated between May 2015-December 2016, inclusive, in two community hospitals in Edmonton using six ketamine infusions of 0.5 mg/kg over 40 min over 2-3 weeks. Data were collected retrospectively from inpatient and outpatient charts. Statistical analysis to investigate clinical predictors of effectiveness included logistic regression analysis using a dependent variable of a 50% reduction in rating scale score at any point during treatment. Results: At baseline, the average treatment resistance was severe, with a Maudsley Staging Method score of 12.1 out of 15, 90.0% were resistant to electroconvulsive therapy, and the average Beck Depression Inventory score was 34.2. The response rate was 44% and remission rate was 16%. As a single predictor, moderate or severe anhedonia at baseline predicted a 55% increased likelihood of response. As a combined predictor, this level of anhedonia at baseline with a diagnosis of bipolar depression predicted a 73% increase in likelihood of response. Conclusion: In a clinical setting, intravenous ketamine showed effectiveness in a complex, severely treatment-resistant, depressed population on multiple medication profiles concurrently. This study gave support to anhedonia and bipolar depression as clinical predictors of effectiveness.
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The N-methyl-d-aspartate receptor (NMDAR) antagonist ketamine has attracted enormous interest in mental health research owing to its rapid antidepressant actions, but its mechanism of action has remained elusive. Here we show that blockade of NMDAR-dependent bursting activity in the 'anti-reward center', the lateral habenula (LHb), mediates the rapid antidepressant actions of ketamine in rat and mouse models of depression. LHb neurons show a significant increase in burst activity and theta-band synchronization in depressive-like animals, which is reversed by ketamine. Burst-evoking photostimulation of LHb drives behavioural despair and anhedonia. Pharmacology and modelling experiments reveal that LHb bursting requires both NMDARs and low-voltage-sensitive T-type calcium channels (T-VSCCs). Furthermore, local blockade of NMDAR or T-VSCCs in the LHb is sufficient to induce rapid antidepressant effects. Our results suggest a simple model whereby ketamine quickly elevates mood by blocking NMDAR-dependent bursting activity of LHb neurons to disinhibit downstream monoaminergic reward centres, and provide a framework for developing new rapid-acting antidepressants.
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Rationale: Clinical data with 3,4-methylenedioxymethamphetamine (MDMA) in post-traumatic stress disorder (PTSD) patients recently stimulated interest on the potential therapeutic use of psychedelics in disorders characterized by maladaptive memories, including substance use disorders (SUD). The rationale for the use of MDMA in PTSD and SUD is being extended to a broader beneficial "psychedelic effect," which is supporting further clinical investigations, in spite of the lack of mechanistic hypothesis. Considering that the retrieval of emotional memories reactivates specific brain mechanisms vulnerable to inhibition, interference, or strengthening (i.e., the reconsolidation process), it was proposed that the ability to retrieve and change these maladaptive memories might be a novel intervention for PTSD and SUD. The mechanisms underlying MDMA effects indicate memory reconsolidation modulation as a hypothetical process underlying its efficacy. Objective: Mechanistic and clinical studies with other two classes of psychedelic substances, namely cannabinoids and ketamine, are providing data in support of a potential use in PTSD and SUD based on the modulation of traumatic and appetitive memory reconsolidation, respectively. Here, we review preclinical and clinical data on cannabinoids and ketamine effects on biobehavioral processes related to the reconsolidation of maladaptive memories. Results: We report the findings supporting (or not) the working hypothesis linking the potential therapeutic effect of these substances to the underlying reconsolidation process. We also proposed possible approaches for testing the use of these two classes of drugs within the current paradigm of reconsolidation memory inhibition. Conclusions: Metaplasticity may be the process in common between cannabinoids and ketamine/ketamine-like substance effects on the mediation and potential manipulation of maladaptive memories.
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Background Identifying clinical correlates associated with reduced suicidal ideation may highlight new avenues for the treatment of suicidal thoughts. Anhedonia occurs across psychiatric diagnoses and has been associated with specific neural circuits in response to rapid-acting treatments, such as ketamine. This analysis sought to evaluate whether reductions in suicidal ideation after ketamine administration were related to reduced levels of anhedonia, independent of depressive symptoms. Methods This post-hoc analysis included treatment-resistant patients with either major depressive disorder (MDD) or bipolar disorder (BD) from several clinical trials of ketamine. Anhedonia was assessed using a subscale of the Beck Depression Inventory (BDI) and the Snaith-Hamilton Pleasure Scale (SHAPS). The outcome of interest was suicidal ideation, as measured by a subscale of the Scale for Suicide Ideation (SSI5), one day post-ketamine administration. Results Anhedonia, as measured by the SHAPS, was associated with suicidal thoughts independent of depressive symptoms both before and after ketamine administration. One day post-ketamine administration, improvements on the SHAPS accounted for an additional 13% of the variance in suicidal thought reduction, beyond the influence of depressive symptoms. The BDI anhedonia subscale was not significantly associated with suicidal thoughts after adjusting for depressive symptoms. Limitations Data were limited to patients experiencing a major depressive episode and may not be generalizable to patients experiencing an active suicidal crisis. Conclusions Suicidal thoughts may be related to symptoms of anhedonia independent of other depressive symptoms. These results have implications for the potential mechanisms of action of ketamine on suicidal thoughts.
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Depression is associated with social risk factors, social impairments and poor social functioning. This paper gives an overview of these social aspects using the NIMH Research and Domain Criteria ‘Systems for Social Processes’ as a framework. In particular, it describes the bio-psycho-social interplay regarding impaired affiliation and attachment (social anhedonia, hyper-sensitivity to social rejection, competition avoidance, increased altruistic punishment), impaired social communication (impaired emotion recognition, diminished cooperativeness), impaired social perception (reduced empathy, theory-of-mind deficits) and their impact on social networks and the use of social media. It describes these dysfunctional social processes at the behavioural, neuroanatomical, neurochemical and genetic levels, and with respect to animal models of social stress. We discuss the diagnostic specificity of these social deficit constructs for depression and in relation to depression severity. Since social factors are importantly involved in the pathogenesis and the consequences of depression, such research will likely contribute to better diagnostic assessments and concepts, treatments and preventative strategies both at the diagnostic and transdiagnostic level.
The N-methyl-d-aspartate (NMDA) receptor antagonist ketamine is associated with rapid but transient antidepressant effects in patients with treatment resistant unipolar depression (TRD). Based on work suggesting that ketamine and lithium may share overlapping mechanisms of action, we tested lithium compared to placebo as a continuation strategy following ketamine in subjects with TRD. Participants who met all eligibility criteria and showed at least an initial partial response to a single intravenous infusion of ketamine 0.5 mg/kg were randomized under double-blind conditions to lithium or matching placebo before receiving an additional three infusions of ketamine. Subsequent to the ketamine treatments, participants remained on lithium or placebo during a double-blind continuation phase. The primary study outcome was depression severity as measured by the Montgomery–Åsberg Depression Rating Scale compared between the two groups at Study Day 28, which occurred ~2 weeks following the final ketamine of four infusions. Forty-seven participants with TRD were enrolled in the study and underwent an initial ketamine infusion, of whom 34 participants were deemed to have at least a partial antidepressant response and were eligible for randomization. Comparison between treatment with daily oral lithium (n = 18) or matching placebo (n = 16) at the primary outcome showed no difference in depression severity between groups (t32 = 0.11, p = 0.91, 95% CI [−7.87, 8.76]). There was no difference between lithium and placebo in continuing the acute antidepressant response to ketamine. The identification of a safe and effective strategy for preventing depression relapse following an acute course of ketamine treatment remains an important goal for future studies.
Objective: There is growing evidence confirming increased inflammation in a subset of adults with depression. The impact of this relationship has mostly been considered in biologically based interventions; however, it also has potential implications for psychological therapies. Cognitive behaviour therapy is the most commonly used psychological intervention for the treatment of depression with theories around its efficacy primarily based on psychological mechanisms. However, cognitive behaviour therapy may have an effect on, and its efficacy influenced by, physiological processes associated with depression. Accordingly, the purpose of this systematic review was to examine the relationship between cognitive behaviour therapy and inflammation. Method: Studies examining the anti-inflammatory effects of cognitive behaviour therapy in people with depression and other medical conditions (e.g. cancer, diabetes and heart disease) were examined. In addition, the relationship between change in inflammatory markers and change in depressive symptoms following cognitive behaviour therapy, and the influence of pre-treatment inflammation on cognitive behaviour therapy treatment response were reviewed. Results: A total of 23 studies investigating the anti-inflammatory effects of cognitive behaviour therapy were identified. In 14 of these studies, at least one reduction in an inflammatory marker was reported, increases were identified in three studies and no change was found in six studies. Three studies examined the relationship between change in inflammation and change in depressive symptoms following cognitive behaviour therapy. In two of these studies, change in depressive symptoms was associated with a change in at least one inflammatory marker. Finally, three studies examined the influence of pre-treatment inflammation on treatment outcome from cognitive behaviour therapy, and all indicated a poorer treatment response in people with higher premorbid inflammation. Conclusion: Preliminary evidence suggests inflammation should be considered within the context of cognitive behaviour therapy, although robust studies examining the relationship are sparse, and heterogeneity between studies and populations examined was high. The potential treatment implications of the bi-directional relationship between inflammation and cognitive behaviour therapy are discussed, and recommendations for future research are proposed.
Depression is a common, devastating illness. Current pharmacotherapies help many patients, but high rates of a partial response or no response, and the delayed onset of the effects of antidepressant therapies, leave many patients inadequately treated. However, new insights into the neurobiology of stress and human mood disorders have shed light on mechanisms underlying the vulnerability of individuals to depression and have pointed to novel antidepressants. Environmental events and other risk factors contribute to depression through converging molecular and cellular mechanisms that disrupt neuronal function and morphology, resulting in dysfunction of the circuitry that is essential for mood regulation and cognitive function. Although current antidepressants, such as serotonin-reuptake inhibitors, produce subtle changes that take effect in weeks or months, it has recently been shown that treatment with new agents results in an improvement in mood ratings within hours of dosing patients who are resistant to typical antidepressants. Within a similar time scale, these new agents have also been shown to reverse the synaptic deficits caused by stress.