The following research data suggests potential detrimental effects of neuroleptics, e.g., clozaril, on learning capacities mediated by hippocampal-prefrontal cortical synapses. Therese Jay et al (2004), in their “Up and down regulation of synaptic strength at hippocampal to prefrontal cortex synapses” in “Prefrontal Cortex: From Synaptic Plasticity to Cognition” edited by Satoru Otani for Kluwer Academic Publishers, note that specific patterns of stimulation applied in the ventral hippocampus (VH) produces long-term potentiation (LTP) or long-term depression (LTD) of stimulated synapses in the prefrontal cortex (PFC), and these forms of plasticity are reversible. The mesocortical dopamine input is an important determinant in synaptic plasticity at the hippocampal-prefrontal synapses. LTP is enhanced in this pathway by an increase in prefrontal dopamine as well as local stimulation of D1 receptors. Cortical dopamine depletion or a specific blockade of D1 receptors results in a dramatic impairment of cortical LTP. Dopamine and D1 receptors are necessary for the expression of synaptic plasticity in the prefrontal cortex. Dopamine blocking agents, such as clozaril which is antagonistic to D1 receptors, could potentially interfere with prefrontal LTP and synaptic plasticity and therefore impair a patient’s learning capacity.
Grace: Thank you for your reply to one of my postings on neurogenesis and factors observed to stimulate such neuronal growth. For someone trained in neuroscience in the 1970s this discovery was quite significant (we had been taught that there is no neurogenesis in the CNS!). I appreciate your comments and would like to offer further observations and thoughts in the Blakian spirit that opposition can be true friendship-a chance of dialogue-to mutually refine and advance our understanding in a field which is still in its infancy. I will first address the fact that I was centering on neurogenesis-BDNF (brain-derived-neurotrophic factor) was only one factor cited. Since you have addressed the latter, let us look at this more carefully. I will quote from various sources in my library, but I highly recommend a new volume sponsored by COST (European Cooperation in the Field of Scientific and Technical Research), “Brain Damage and Repair: From Molecular Research to Clinical Therapy” edited in 2004 by T. Herdegen (from the Institute of Pharmacology, University of Kiel) and J. Delgado-Garcia (Department of Neurosciences, University Pablo de Olavide, Sevilla) for Kluwer Academic (it costs about $180 but it is quite worth the price). Neurotrophic factors (NGF, BDNF, NT-3, 4, & 5) are enhanced after brain injury, but also clearly depressed by’ psychogenic’ stress and anxiety. In the hippocampus, changes in BDNF mRNA (messenger RNA) are particularly intense, increasing more than six-fold in the dentate gyrus within 30 minutes of seizure induction (thus the findings related to a variant of ECT). However, the interpretation of this mRNA upregulation has significant limitations due to lack of sensitive methods for neurotrohin localization or any predictable relationship between mRNA and protein levels. The role of BDNF in post-synaptic modulation of synaptic transmission and synaptic plasticity in the hippocampus is clearer. I will not go into the details which are too lengthy but the end result is facilitation of LTP (long-term potentiation-the study of which in regard to memory won Eric Kandel a Nobel prize) induction in the postsynaptic dentate granule cells in the hippocampus. BDNF, the most widely distributed and abundant in the CNS, in addition to playing a role in cell differentiation and development (therefore BDNF- you suggested is just a response to neuronal injury-is not just a response to neuronal insult), it is required for the survival and function of neurons in the CNS. Stress impairs the expression of BDNF, decreases neurogenesis in the adult hippocampus, and can be neurotoxic in many neural regions. As I mentioned in the posting to which you have responded to, the atypical antidepressant, tianeptine, blocks the stress (‘psychogenic’ stress is included)- induced atrophy of CA3 apical dentrites (neuronal atrophy is generally thought to be not a positive result of stress, with which I concur-clearly, it is adaptive over the short-term, and much of it may be reversible-see the research of Sapolsky at Stanford University-however, it is thought by many, that it could reach a point of irreversibility-and that is why neurogenesis in compensation for stress-induced cell loss is a positive process). I must add that there is research which demonstrates that antidepressants can also lead to reduced LTP (learning & memory) in the hippocampus. Your interesting comment that perhaps, the increase in BDNF after AD therapy is evidence of a compensatory reaction to injury/insult should be taken seriously, however, BDNF is not the only factor leading to neurogenesis. As for your comment that neurogenesis in itself may not be positive, I think the weight of the evidence that chronic and profound stress/anxiety can lead to cellular atrophic processes as well as cell loss, leads me to believe that neurogenesis, on the whole, is probably more beneficial than not. Further, I believe, as a hunch, that it is best to promote neurogenesis through more ‘natural’ channels (e.g., reducing stress by exercise, which also induces neurogenesis- plus, relaxation, psychotherapy, secure attachments, provision of more enriched environments-the latter being a robust predictor of the birth of new neurons, etc.) As with most things pertaining to our CNS, it is best not to be a reductionist (to try to get the ‘whole’ picture) and to acknowledge that we still know all too little about the human psyche/brain, its capacity to become ill as well asrecover.
Brian Koehler--New York
I am in the process of reading several new books which I would like to recommend to our ISPS members. I have already noted Michael Eigen’s (2004)“The Sensitive Self” published by Wesleyan University Press. This is a very involving, creative and ‘sensitive’ portrayal of the human condition and the deeper processes of psychotherapy. As I once mentioned to Mike, when I first heard him speak many years ago at an NYU Postdoctoral colloquium, my wife and I thought he was quite original-his own unique mix of Bion, Winnicott, Lacan & Allen Ginsberg-he did remind us of the beat poets of the late 1950’s and early 1960’s in downtown NYC.
Another outstanding volume is “In Pursuit of Psychic Change: The Betty Joseph Workshop” edited by Edith Hargreaves & Arturo Varchevker in 2004 for Brunner-Routledge. This volume reminds me of why I am so influenced by the Kleinians and Post-Kleinian clinicians/theorists. Melanie Klein ‘s work still moves me in a very deep place. Once when giving a memorial tribute to Herbert Rosenfeld at an ISPS meeting in Washington DC, Murray Jackson, the panel moderator, stated: Melanie Klein brings the psychotic patient to you (parenthetically, Saloman Resnik, a former analysand of Rosenfeld and colleague of Melanie Klein, remarked on the latter’s sense of humor-which is relatively unknown-she is usually portrayed as a very belligerent person-like all of us, I am sure she had many sides). This volume, although not dealing specifically with the subject of psychosis-since Post-Kleinians assume a psychotic part of the personality in all of us-offers much of value to ISPS clinicians. Betty Joseph, in a host of papers including on patients addicted to near-death experiences and difficult to reach patients, pays very close attention to the emotional processes going on, or not going on, in the room between the two therapy participants, how the patient is ‘using’ the analyst to avoid making contact with deeper aspects of one’s own emotions and being. The crucial work of Harold Searles adds to this the element of mutuality, how the analyst may be using the analysand to avoid painful countertransference experience. One very helpful aspect of the Post-Kleinian approach is viewing the result of ongoing lack of emotional containment by caregivers: the child thinks in ‘beta elements,’ i.e. thoughts are experienced as concrete persecutory objects indistinguishable from external objects into which they are ‘projected.’ For Bion, the absent object is a persecutory one (for good neurobiological reasons). Separation between self and object is very difficult for the person to maintain, or as Hanna Segal maintains, there is a conflation between symbol and symbolized (Segal once communicated to me that she thought her greatest contribution to psychoanalysis was this theory she called the symbolic equation).
To illustrate these dynamics, I will cite a recent vignette from my practice: I am working with one highly delusional and chronically paranoid man who constantly experiences others as trying either to literally rape him or murder him by stealing various body parts-he is hooked up to a very persecutory ‘influencing machine’ (see the work of V. Tausk). I am sure this is so in the transference. He reports growing up in a small family that had no time for him (parents had to work long hours to make ends meet and when they were home, were too tired to even speak with their son-dinners were always in silence). In the transference, I am sometimes him trying to break through the impermeability of the uncontaining objects which refuse containment and emotional reciprocity. My comments and interpretations are hatefully dismissed. His internal persecutory thoughts are experienced as concrete objects in need of evacuation. Speaking to his non-psychotic part gets us nowhere-his mind is ‘hijacked’ by an omnipotent psychotic part of his personality that is as impenetrable as were his very removed caregivers. Separation is a significant trauma for him, he has a deep sense of unbearable loneliness and persecutory isolation (the indifference of others is soul-murder for him).
Over the years, despite unmoveable paranoia, I sustain myself in the relationship with the hope that he will be able to let me in enough to make deeper contact with the state of his mind and internal/external objects which, I believe and have good evidence for, are in a damaged state partly due to his hateful attacks on them secondary to his being dropped from the mind and heart of his primary attachment figures. To accomplish this, I think Searles and Benedetti are correct, one must steadfastly live through the ‘pathological’ paranoid symbiosis in order to arrive at anything resembling a healthy mutually dependent, therapeutic symbiosis. I realize that the latter point of the mutually dependent nature of the relationship and symbiosis is contested by many analysts, but in my experience, I believe it to be true and acknowledgment of it in some way is truly helpful to set in motion these symbiotic processes leading to greater capacities to ‘take in’ the other without jeopardizing the ‘within,’ i.e., to integrate separateness and relatedness simultaneously.
Brian Koehler--New York