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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
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
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.
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Table 1: Hypotheses on specific ways to combine ketamine and psychotherapy
Neuroplasticity in human
reward pathways !
Bias toward negative
Effects on hippocampus
and prefrontal cortex
Disruption of fear