Psychotherapy: A Neurobiological Intervention?

I just read Dr. Nasrallah’s editorial in the December 2013 issue of Current Psychiatry, entitled “Repositioning psychotherapy as a neurobiological intervention.” His point is well taken about psychotherapy’s role in treating a variety of psychiatric disorders. It actually does change the brain. Although I’m not so sure about whether it immediately causes neuroplastic changes, one of our psychiatry residents told me about a couple of recently published papers showing that psychotherapy’s effectiveness may be mediated by neuroplastic changes induced by serotonergic antidepressants [1,2].

The first article by Castren is a very readable and exciting review of studies showing that selective serotonin reuptake inhibitor antidepressants may set the stage for change induced by psychotherapy by inducing a “juvenile-like plasticity” in the adult cortex. The first paragraph of the introduction provides an overview of what the author proposes:

The brain processes sensory information in neuronal networks that are shaped by experience, particularly during early life, to optimally represent the internal and external milieu. Recent surprising findings have revealed that antidepressant drugs reactivate a window of juvenile-like plasticity in the adult cortex. When antidepressant-induced plasticity was combined with appropriate rehabilitation, it brought about a functional recovery of abnormally wired neuronal networks. These observations suggest that antidepressants act permissively to facilitate environmental influence on neuronal network reorganization and so provide a plausible neurobiological explanation for the enhanced effect of combining antidepressant treatment with psychotherapy. The results emphasize that pharmacological and psychological treatments of mood disorders are closely entwined: the effect of antidepressant-induced plasticity is facilitated by rehabilitation, such as psychotherapy, that guides the plastic networks, and psychotherapy benefits from the enhanced plasticity provided by the drug treatment. Optimized combinations of pharmacological and psychological treatments might help make best use of existing antidepressant drugs and reduce the number of treatment-resistant patients. The network hypothesis of antidepressant action presented here proposes that recovery from depression and related mood disorders is a gradual process that develops slowly and is facilitated by structured guidance and rehabilitation.

Castren’s conflict of interest statement reveals he’s received research support from Orion Pharma and that he’s a shareholder and advisor at Hermo Pharma. He also holds a patent on the use of antidepressant to treat amblyopia, which provides a sort of template for his hypothesis on how antidepressants might also induce neuroplasticity of the brain in depressed patients. In part, this depends on the network hypothesis of brain function.

And another implication of the network hypothesis that Castren describes is that it might figure importantly in other neuropsychiatric conditions besides depression. The psychiatry resident who alerted me to the articles wondered if SSRIs coupled to cognitive rehabilitation might be useful for helping patients recover from the often-seen persisting cognitive impairment resulting from episodes of delirium.

The other paper by Oved and colleagues, while open access, is less digestible but suggests a similar idea, “…our working hypothesis supports a role for ITGB3 in the treatment of depression. Moreover, our findings and model, suggestive of a tentative role for elevated expression of cell adhesion proteins for remission from depression, may in part explain the enigmatic slow onset of the antidepressant action of SSRI drugs. Elucidating the roles of ITGB3, CHL1 and additional cell adhesion proteins in the mode of action of SSRI antidepressants requires studies with animal models for depression and eventually clinical studies.”

It’s important to realize that much of this work is still in the experimental stages. And simply giving SSRIs normal subjects without neuropsychiatric disorders would not necessarily lead to enhanced mood and could lead to maladaptive plasticity if given to persons who struggle in a toxic environment. Context is almost everything.

So, Dr. Nasrallah’s ideal for repositioning psychotherapy as a neurobiological intervention could be realized, maybe even in our lifetime.

References:

1. Castrén, E. (2013). “Neuronal network plasticity and recovery from depression.” JAMA Psychiatry 70(9): 983-989.

The brain processes sensory information in neuronal networks that are shaped by experience, particularly during early life, to optimally represent the internal and external milieu. Recent surprising findings have revealed that antidepressant drugs reactivate a window of juvenile-like plasticity in the adult cortex. When antidepressant-induced plasticity was combined with appropriate rehabilitation, it brought about a functional recovery of abnormally wired neuronal networks. These observations suggest that antidepressants act permissively to facilitate environmental influence on neuronal network reorganization and so provide a plausible neurobiological explanation for the enhanced effect of combining antidepressant treatment with psychotherapy. The results emphasize that pharmacological and psychological treatments of mood disorders are closely entwined: the effect of antidepressant-induced plasticity is facilitated by rehabilitation, such as psychotherapy, that guides the plastic networks, and psychotherapy benefits from the enhanced plasticity provided by the drug treatment. Optimized combinations of pharmacological and psychological treatments might help make best use of existing antidepressant drugs and reduce the number of treatment-resistant patients. The network hypothesis of antidepressant action presented here proposes that recovery from depression and related mood disorders is a gradual process that develops slowly and is facilitated by structured guidance and rehabilitation.

2. Oved, K., A. Morag, et al. (2013). “Genome-wide expression profiling of human lymphoblastoid cell lines implicates integrin beta-3 in the mode of action of antidepressants.” Transl Psychiatry 3: e313.

Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for major depression. However, the link between inhibition of serotonin reuptake and remission from depression remains controversial: in spite of the rapid onset of serotonin reuptake inhibition, remission from depression takes several weeks, presumably reflecting synaptogenesis/neurogenesis and neuronal rewiring. We compared genome-wide expression profiles of human lymphoblastoid cell lines from unrelated individuals following treatment with 1[thinsp][mu]M paroxetine for 21 days with untreated control cells and examined which genes and microRNAs (miRNAs) showed the most profound and consistent expression changes. ITGB3, coding for integrin beta-3, showed the most consistent altered expression (1.92-fold increase, P=7.5 [times] 10-8) following chronic paroxetine exposure. Using genome-wide miRNA arrays, we observed a corresponding decrease in the expression of two miRNAs, miR-221 and miR-222, both predicted to target ITGB3. ITGB3 is crucial for the activity of the serotonin transporter (SERT), the drug target of SSRIs. Moreover, it is presumably required for the neuronal guidance activity of CHL1, whose expression was formerly identified as a tentative SSRI response biomarker. Further genes whose expression was significantly modulated by chronic paroxetine are also implicated in neurogenesis. Surprisingly, the expression of SERT or serotonin receptors was not modified. Our findings implicate ITGB3 in the mode of action of SSRI antidepressants and provide a novel link between CHL1 and the SERT. Our observations suggest that SSRIs may relieve depression primarily by promoting neuronal synaptogenesis/neurogenesis rather than by modulating serotonin neurotransmission per se.

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Comments

  1. I thought it already was realized by Kandel back in 1979 and his classic article Psychotherapy and the Single Synapse? The problem with repositioning psychotherapy as a neurobiological intervention based on plasticity is that it is no more neurobiological than learning to play the piano, pumping iron, or learning to speedskate. It is just another experience dependent change in connectivity.

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