Combining Ketamine with Psychotherapy for Treatment of 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 blog outlines some mechanistic hypotheses, how Behavioral Activation, Trauma-Focused Psychotherapies and Humanistic Psychotherapy may specifically prolong ketamine’s antidepressant effects.

Ketamine promotes the rapid growth of neuronal processes and the formation of synapses, a process that constitutes the cellular basis of learning. People with treatment-resistant depression may have stopped benefiting from therapy because their capacity to learn is impaired by stress-induced neuronal atrophy.  A group at Yale University has published preliminary data suggesting that cognitive behavioral therapy can act synergistically with ketamine to prolong the antidepressant effects of ketamine infusions. Anecdotally, many of us know that ketamine enhances the psychotherapeutic process by accelerating the transference, enhancing openness, and fostering empathy between the patient and provider. It also tends to reduce inhibitions, making it easier to talk about difficult subjects.

There is evidence that cognitive behavioral therapy pairs well with ketamine. Gregor Hasler wrote a brief theoretical review of psychotherapies appropriate for ketamine treatment in 2019.1 For instance, as increased energy and initiative are hallmarks of the ketamine response, behavioral activation is a good fit. Ketamine may disrupt fear memory consolidation and strengthen the formation of extinction memory which could help explain its usefulness in exposure-based therapies. Humanistic psychotherapy and interpersonal psychotherapy are also sound methodologies.

Blood pressure needs to be monitored before dosing and at the close of the session. If the patient’s baseline BP is somewhat elevated, the provider in some cases may want to assess it 20-30 minutes after dosing. Blood pressure checks should be done routinely at the initiation of therapy and after dosage increases. A transient hypertensive response to ketamine is common, as is dissociation, mood elevation or anxiety, nausea, vomiting, dizziness, sedation, blurred vision, and numbness.

Recently, it was demonstrated that ketamine can change body feelings and induce subjective lightness and floating, 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. In some 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 encourages studies on psychosocial interventions to prolong its efficacy. Research on ketamine’s effect on cognition will base such efforts on empirically driven hypotheses.

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