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Toward specific ways to combine ketamine and psychotherapy in treating depression

June 2019
CNS spectrums 25(3):1-3

DOI:10.1017/S1092852919001007

Authors:

Université de Fribourg

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.

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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

Switzerland

gregor.hasler@unifr.ch

Abstract

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.

Text

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.

2. Cuijpers P, van Straten A, Warmerdam L, Andersson G. Psychotherapy versus the combination of

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.

2017;51(6):565-582.

9. Hasler G, Drevets WC, Manji HK, Charney DS. Discovering endophenotypes for major depression.

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.

2011;25(11):1453-1461.

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

Ketamine’s

neurobiological effect

Ketamine’s clinical

effect

Ketamine’s

psychological effect

Combination with

psychotherapy

Neuroplasticity in human

reward pathways !

Anhedonia¯

Reinforcement

learning!

Behavioral Activation

Anti-inflammatory

effects

Social avoidance¯

Rejection sensitivity¯

Therapeutic bond!

Interpersonal

Psychotherapy etc.

Lateral habenula

bursting¯

Pessimistic thinking¯

Bias toward negative

information¯

Cognitive Bias

Modification

Effects on hippocampus

and prefrontal cortex

Specific cognitive

deficits

Disruption of fear

memory

Trauma-focused

psychotherapies

Neuroplasticity in

thalamocortical circuits!

Perception!

Memory!

Personality dimension

Openness!

Humanistic

psychotherapies

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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.

The altered-state-of-consciousness (ASC) 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

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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.

Ketamine blocks bursting in the lateral habenula to rapidly relieve depression

Article

Full-text available

Feb 2018
NATURE

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.

Psychedelics and reconsolidation of traumatic and appetitive maladaptive memories: focus on cannabinoids and ketamine

Article

Full-text available

Feb 2018
PSYCHOPHARMACOLOGY

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.

Anhedonia as a Clinical Correlate of Suicidal Thoughts in Clinical Ketamine Trials

Article

Full-text available

Apr 2017

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.

Social functioning in major depressive disorder

Article

Full-text available

Jul 2016

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.

Lithium continuation therapy following ketamine in patients with treatment resistant unipolar depression: a randomized controlled trial

Article

Mar 2019
NEUROPSYCHOPHARMACOL

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.

Cognitive behaviour therapy and inflammation: A systematic review of its relationship and the potential implications for the treatment of depression

Article

Apr 2017

Adrian L Lopresti

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.

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

Article

Mar 2016

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.