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.

Pharmacologic synergy

Before discussing specific combination and augmentation strategies for treatment resistance, it is important to highlight 2 basic principles of psychopharmacology: the first is to combine mechanisms, not drugs. Combining drugs with different mechanisms promotes "pharmacologic synergy,"⁵ whereas combining drugs with similar mechanisms may simply promote unnecessary redundancy. The second principle is understanding the mechanisms underlying the drugs' side effects. Successfully combining drugs with opposing side-effect profiles will promote tolerability. In fact, the best drug combinations obey both rules, namely, they offer a synergistic boost to efficacy because of the different mechanisms of action of each agent and in- creased tolerability because of side ef- fects that cancel one another out.

Strategies to address treatment resistance

Many strategies are used to address treatment resistance in psychiatric patients, including adjunctive treatment with thyroid hormone, lithium or anticonvulsant mood stabilizers, omega-3 essential fatty acids, bupropion, psychostimulants, atypical antipsychotics, buspirone, adrenal hormones, sex hormones, aerobic exercise, B-complex vitamins, folate, and other nutrient supplementation. Unfortunately, there are few randomized controlled studies in the literature to guide us in our treatment choices. Some of the most common augmentation strategies for de- pression (such as supplementing a first-line drug with the noradrenergic/ dopaminergic agent bupropion, psychostimulants like methylphenidate, and atypical antipsychotics like risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole) are those with the least evidence from controlled studies.¹ On the other hand, augmentation with thyroid hormones and lithium, 2 strategies for which there is substantial evidence from controlled studies, is much less common.¹

Despite the relative lack of controlled studies for the atypical antipsychotics, there are now a few good studies that speak to their efficacy in treatment resistance. The findings of a recent randomized, double-blind, placebo- controlled trial of 542 patients with either bipolar I or II depression taking up to 600 mg of quetiapine daily for 8 weeks showed that this atypical antipsychotic was efficacious for the treatment of acute bipolar depression and, because of its lower incidence of extrapyramidal side effects and reduced risk of tardive dyskinesia, was well tolerated.⁶ Based on this and several other studies, it has been suggested that some of the atypical antipsychotics may be more aptly termed "broad-spectrum psychotropics," because they are able to address affective states, such as mania and depression, along with psychotic symptoms.⁷ In any event, much more research needs to be done to document the effectiveness of the atypical antipsychotics as adjunctive treatments for refractory depression.

Thyroid hormone, particularly triiodothyronine, has been used to augment and to accelerate the effectiveness of traditional antidepressants, particularly those that mediate serotonergic neurotransmission.^8,9 Thyroid hormones are particularly useful because of their favorable safety and side-effect profiles. Interestingly, there is even evidence to suggest that supplemental thyroid hormone administered to patients with depression unresponsive to first-line antidepressants can boost the effectiveness of the antidepressant even when the patient is not overtly hypothyroid.⁵ Thyroid hormone, particularly thyroxine, has sometimes been used successfully for rapid-cycling bipolar disorder that was otherwise resistant to mood stabilizers.¹⁰ The mechanism of action is presumed to involve either potentiation of neurotransmission at the level of the cell membrane or stimulation of gene transcription at the nuclear level.⁸

Administration of dehydroepiandrosterone (DHEA), an adrenocortical hormone secreted by the hypothalamic-pituitary-adrenal stress axis, appears to offer some promise for protection from depression, even in patients without documented adrenal insufficiency.¹¹ In a double-blind trial, after 6 months of using 50 mg of DHEA per day, a "remarkable increase in perceived physical and psychological well-being" was reported in both men and women.¹² In another double-blind, randomized, placebo-controlled study involving men and women with midlife-onset depression, after only 6 weeks of taking up to 90 mg of DHEA per day, subjects showed a statistically significant improvement in depression (both major and minor).¹³ The efficacy of long-term DHEA treatment is not known, nor do we know how realistic it is to be concerned that the exogenous administration of DHEA will, over time, suppress the body's endogenous produc- tion of it. Nonetheless, adjunctive treatment with DHEA does appear to offer some promise, so further studies are warranted.

Epidemiologic and treatment studies^14-21 support the following hypotheses regarding the association between omega-3 polyunsaturated fatty acids (PUFAs) and depression: (1) deficits in dietary-based PUFAs may be a contributing factor in mood disorders; (2) low plasma concentrations of PUFAs are linked to depression; and (3) supplementation with at least 1 g daily of eicosapentaenoic acid (EPA), an omega-3 PUFA, provides some therapeutic benefit. It remains unclear whether omega-3 supplementation is effective for patients with depression in general or only for those with abnormally low concentrations of PUFAs.^14-21 More evidence is also needed to determine which omega-3 fatty acid, EPA or docosahexaenoic acid, will provide greater benefit.

Hormesis and treatment resistance

No discussion of treatment resistance would be complete without at least acknowledging the possible role played by hormesis.^22,23 Formerly called the Arndt-Schulz Law, the hormetic dose-response model is thought to describe the biphasic relationship between dose and response--low-dose stimulation and high-dose inhibition, or vice versa. It is a little-known fact that there is not always a simple linear relationship between the dose of a drug and the clinical response: it is not always the case that the higher the dose, the more effective the drug. Because of this hormetic effect, higher doses--beyond a certain point--may actually be less effective (and not because the drug becomes less well tolerated). In fact, it is estimated that about 50% of drugs prescribed by physicians (including the psychotropic medications prescribed by psychiatrists) demonstrate the so-called hormetic effect (E. Calabrese, written communication, September 2006).

With respect to the mechanism underlying hormesis, Calabrese hypothesizes that hormesis occurs as a result of "modest overcompensation" by the body in the face of threatened disruption to homeostasis. In other words, any stressor that threatens to disrupt the body's homeostatic equilibrium may prompt activations of the body's regulatory systems in an effort to return the body to homeostatic balance. For example, a low-dose stressor (such as mild to moderate exercise) will stimulate the hypothalamic-pituitary-adrenal stress axis and the autonomic nervous system, initially energizing the body and resulting in feelings of increased well-being; but prolonged or excessive exercise will ultimately deplete the body's energetic and nutrient reserves and lead to compromise in functioning, fatigue, and dysphoria.

One of the most impressive and most often cited clinical trials on the efficacy of omega-3 fatty acids in the treatment of unipolar depression may provide a good example of the hormetic effect.¹⁸ In this elegantly designed 12-week, double-blind, placebo-controlled study, patients receiving ethyl-EPA were divided into 3 dosage groups (1, 2, and 4 g/d). All the participants had experienced persistent depression despite treatment with standard antidepressants at adequate dosages. The findings from this study showed that the patients receiving 1 g of EPA per day had the best outcome (with more than half achieving a 50% reduction on Hamilton Depression Rating Scale scores). Interestingly, the authors of the study found that the group receiving 2 g/d "showed little evidence of efficacy."²² Obviously, there are many ways to interpret this surprising finding, but one possible explanation involves the hormetic (biphasic) effect of low-dose stimulation and high-dose inhibition.

We must, therefore, always take into consideration the potential impact of hormesis on dosing. If a patient with depression taking 20 mg of fluoxetine is responding only minimally to treatment, we almost always assume a linear relationship between dose and response and so go higher in our dosing, increasing perhaps to 30 mg, 40 mg, or more in pursuit of the desired antidepressant effect (sometimes stopping only after the drug's side effects become so unmanageable that the patient can no longer tolerate the drug). Indeed, because of a patient's genetic uniqueness and biochemical individuality, a particular patient may experience only mild improvement on a regimen of 20 mg of fluoxetine but significant improvement on a regimen of 10 mg, this latter dose offering obviously the optimal antidepressant effect. Again, it is the hormetic effect of the drug that accounts for this biphasic response of lower-dose (10 mg of fluoxetine) stimulation and higher-dose (20 mg of fluoxetine) inhibition, that is, lower-dose effectiveness and higher-dose ineffectiveness. In essence, more is not necessarily better!

Most remarkable of all is Calabrese's finding that when hormesis is involved, "synergy" occurs with respect not to response but to dose. When combinations of drugs demonstrate the hormetic effect, clinical effectiveness may occur much more easily than anticipated--because of hormesis. This is clearly an instance of the earlier-referenced holism, "the whole is greater than the sum of its parts." Inasmuch as combination/ augmentation strategies figure prominently in our repertoire of strategies for treatment resistance, it is therefore imperative that we appreciate the potential synergistic impact of the hormetic effect on drug combinations.

I began this article by suggesting that if we are to be more broadly effective in our work with patients, then we need to consider adopting a more holistic perspective, one that takes into account the collective and synergistic impact of the many different factors involved in regulating mental health. In addition to considering the levels of neurotransmitters in our patients' brains, it is crucial that we look at additional factors--those that tell a story about the patient (namely, other regulatory systems in the body, comorbid disease states, and individual genetic make-up and biochemical uniqueness) and those that tell a story about the drugs themselves (namely, their potential to demonstrate the hormetic effect).

I conclude, therefore, with the reminder that when we use augmentation/ combination strategies for treatment resistance, we must never lose sight of the big picture, that is, we must be ever attuned to the complicated, often unexpected synergy that exists between confounding factors presented by the patient and confounding factors in the medication regimens we prescribe. By the same token, if we are to stand a chance of improving on the one-third rule, then we must remain acutely aware of the complex relationships between the different drugs in our psychopharmacologic armamentarium.

Dr Stark is clinical instructor in psychiatry, department of continuing education, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, and adjunct faculty, Center for Psychoanalytic Studies, Massachusetts General Hospital, Harvard Medical School, Boston. She is also the author of several books on resistance and the modes of therapeutic action.

She reports that she has no conflicts of interest concerning the subject matter of this article.

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