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Neurotransmitters, Pharmacologic Synergy, and Clinical Strategies

Neurotransmitters, Pharmacologic Synergy, and Clinical Strategies

During my psychiatric residency, I was taught (only somewhat tongue-in-cheek) the one-third rule, namely, that with respect to psychotherapeutic intervention, one third of our patients would get better, one third would stay the same, and one third would get worse. Later I was to learn that this same one-third rule applied to psychopharmacologic intervention as well.

Although studies now suggest that some psychotropic medication regimens have a somewhat higher success rate than the one-third rule would have predicted, psychiatrists are still left with the problem of why it is that only one third to one half of patients who are treated get better, and why fewer still sustain that improvement over time. Even with higher doses, longer drug trials, newer generations of drugs, broader targeting of neurotransmitters and their receptor sites, more ingenious methods of drug administration, and more creative combinations of the various drugs, more than half our patients have psychiatric symptoms that simply do not respond to our interventions.1,2 How does a psychiatrist make sense of this apparent treatment resistance?

Let us start by making explicit the implicit hypothesis underlying mental health and mental illness: that mood regulation is predominantly a story about the excitatory and inhibitory neurotransmitters in our brains and that "aberrant" feelings can therefore be conceived of as representing aberrant or imbalanced levels of these chemical mediators. Neurotransmitters are thought to trigger a molecular cascade that begins with the interaction of the neurotransmitter with its postsynaptic receptor and ends with the activation or deactivation of specific genes responsible for the regulation of mood.3 Particularly important are those genes involved in the synthesis of neurotrophins, like brain-derived neurotrophic factor.4

Whatever the ultimate impact of the neurotransmitter on intracellular signal transduction pathways4 and the expression of critical genes, the targeting of specific neurotransmitters has been the mainstay of psychopharmacologic intervention. Pharmacology is based on the premise that if a regulatory pathway is involved, then a physician can selectively intervene with drugs that will either stimulate or block any step in the chain. As it happens, most of the psychotropic agents (whether antidepressants, mood stabilizers, antipsychotics, anxiolytics, sedative-hypnotics, psychostimulants, or cognitive enhancers) selectively target the first step in this regulatory pathway, the neurotransmitters.

What some cutting-edge psychiatrists are beginning to recognize, however, is that so-called treatment re- sistance may well be the result of reductionism--a too-narrow focus on imbalanced neurotransmitter levels and a failure to consider not only the underlying reasons for these imbalances but also, more generally, the contributions of other biochemical and physiologic factors to the overall picture. State-of-the-art psychopharmacology is therefore espousing a more holistic approach, one that is both broader-based and more medicalized, taking into account, as it does, not just other regulatory systems in the body (such as the endocrine, immune, and autonomic nervous systems) but also the interactions between and among these different systems.

Here I am speaking to the issue of medical comorbidity, that is, the simultaneous presence of fixed-name disease as a confounding factor in psychiatric disorders. I am also speaking, however, about the need to focus on how effectively the body's regulatory systems are accomplishing their job of maintaining the body's homeostasis, thereby making possible both a state of internal balance and feelings of emotional well-being. Even though this more expansive approach involves consideration of these other "medical" parameters, such a multipronged approach is, I believe, still well within the scope of what we, as psychiatrists, can reasonably and affordably offer our patients--and we may find that it produces much more satisfactory results.

In essence, I am advocating a holistic approach to mental health, one that focuses not only on individual components but also on what emerges when those components are considered collectively and synergistically. The "whole" that then arises will transcend the sum of its parts. A holistic or systemic approach deeply appreciates that our resilience and vitality depend on not only levels of critical brain chemicals but also, more generally, the functionality of the many regulatory systems responsible for maintaining the body's overall homeostatic balance. From this it follows that unless the health of all these regulatory systems is addressed and a state of harmonious integration within, between, and among them is restored, our patients' psychiatric symptoms may well prove refractory despite our best efforts to regulate the levels of the various neurotransmitters in their brains.

Our patients' mental health, therefore, is not only a story about their levels of serotonin, dopamine, and norepinephrine but also, for example, their levels of immune cell mediators, especially proinflammatory cytokines (traditionally the province of immunologists) and their hormone levels, which fluctuate over the course of a day, a month, a lifetime (traditionally the province of endocrinologists and gynecologists). In fact, psychoneuroimmunology (introduced in 1975 by Robert Ader and Nicholas Cohen at the University of Rochester) is a relatively new field that studies the interactions among the brain, cognitive function, mood, the endocrine system, and immune activation.

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