Primary Psychiatry. 2004;11(12):33-40

Abstract

Menstrually related disorders affect a significant number of women of reproductive age. The pathobiology of menstrually related disorders, specifically premenstrual syndromes, involve multifaceted interactions between processes of the central nervous system, hormones, and other modulators. These interactions include gonadal hormones, their metabolites, and several neurotransmitters and neurohormonal systems, including serotonin, γ-aminobutyric acid, and rennin-angiotensin-aldosterone system. In vulnerable women, response of these systems to normal fluctuations of gonadal hormones may contribute to expressions of symptoms. Disrupted homeostasis and impaired adaptation may be an important underlying mechanism.

Introduction

Menstrually related symptoms may be considered to be normal as they have been reported in up to 80% of women of reproductive age.^1-3 While menstrually related disorders may be associated with several phases of the menstrual cycle, eg, menses and the periovulatory period, a focus of clinical and research endeavors has been on disorders occurring during the late luteal phase or the premenstrual period of the menstrual cycle. Premenstrual syndromes (PMS) may be mostly physical or mostly mental. However, as long as the affected woman has at least one symptom that is severe enough to cause impairment, her PMS is considered to be a disorder.⁴ If the mental symptoms predominate, are very severe, and are associated with impairment, then the patient is classified as having premenstrual dysphoric disorder (PMDD) which may be viewed as a severe subtype of PMS. Severe and debilitating premenstrual mood and behavior symptoms that reach the severity of a disorder were reported in at least 3% to 10% of women with PMS,^4-8 with recent reports of clinically relevant dysphoric PMS affecting as many as 18% of young women.⁹

The importance of PMS and PMDD is underscored by the demonstration that the burden associated with PMDD is comparable to that of major depressive disorder (MDD).¹⁰ The diagnostic aspects of PMS/PMDD have been discussed in many publications^11-12 and elsewhere in this issue.¹³

This article summarizes several recent papers on the pathobiology of PMS.^14-17 It emphasizes multifaceted interactions between several processes of the central nervous system (CNS), hormones, and other modulators pointing to an integration between genetics and “dynamically evolving vulnerability,”which involves both negative and positive environmental and hormonal inputs.^18-20

What May Be Learned from Efficacy of Treatments?

Menstrually related symptoms and disorders exhibit a multifactorial nature and have resulted in a variety of treatment interventions. Ideally, treatment should be based on known etiology and pathophysiology, which remains only an assumption in the case of PMDD/PMS (as is the case with most mental disorders). One may infer that if a specific treatment modality is more efficacious than placebo, then its presumed biological action “corrects” an abnormality that is relevant to the etiology of the disorder in focus. The rationale of this assumption may be challenged on several grounds that are beyond the discussions here. However, since that assumption is currently prevailing in psychiatry, its possible implication for the etiology of PMS/PMDD will be discussed.

The majority of treatments investigated for mood-related disorders and specifically for PMS/PMDD are either functional (eg, hormonal manipulations) or symptomatic (eg, antidepressant therapy).^15,17,21,22 Several therapeutic interventions for PMS/PMDD have been systematically evaluated by two recent consensus processes focusing on evidence from randomized trials in order to determine intervention efficacy.^23,24 A modified summary of the consensi findings regarding effective treatments is presented in the Table. Conclusions from several more recent papers are included, as well as the authors’ opinions on lithium, carbamazepine, and other modalities that were not discussed by the consensus panels. For implications about pathobiology, treatment modalities that have not been shown to be effective are also of interest and are presented in the Table.

The efficacious treatment modalities may be interpreted as suggesting the following underlying mechanisms: Suppression of ovulation is highly effective as a treatment for PMS/PMDD, but dependent on mode and dosing.²⁵ The implication is that ovulation, or ovulation-related processes, are an important factor in the pathobiology of PMS. Fluctuations in levels of gonadal hormones contribute to symptom formation. When using hormonal contraception to suppress ovulation and to control fluctuations, some progestogens (including progesterone) might be a causative factor to symptoms. In addition, some progesterone metabolites may even cause a positive effect, suggesting hormonal contribution to pathobiology of PMS beyond the ovulation per sé.

Serotonergic antidepressants are an effective treatment for PMDD also when they are administered only intermittently during the entire luteal phase.^26,27 Serotonergic antidepressants have proven less effective when administered only during the late luteal-symptomatic phase.²⁸ Norepinephrine (NE) reuptake inhibitors have been reported to be less effective,²⁹ or they may be effective in only a smaller group of women with PMDD. This may imply that the serotonergic system is involved in the pathobiology of PMDD while the NE system is less important in most women. Yet, it has been shown that one third of women who meet criteria of PMDD do not respond to serotonergic antidepressants. This implies that there may be smaller subgroups of women with PMDD who have a non serotonergic neurotransmitter or other abnormalities, such as NE or γ-aminobutyric acid (GABA) underlying abnormalities. A diversity of subgroups of PMS may also be implied by the efficacy of bromocriptine, which is limited only to premenstrual mastalgia.³⁰ The GABA system might also be implicated by the demonstrated efficacy of alprazolam (although this is still controversial).^31,32

Some insufficient or conflicting data on treatment efficacy involve compounds, such as calcium, magnesium, several vitamins (eg, vitamin B₆), mefenamic acid, prostaglandine antagonists, and others, that may contribute or serve as co-factors in the functioning of multifaceted processes. Social support, relaxation, cognitive-behavioral interventions, other interventions not completely evidence proven, and general well-being interventions may point to the importance of internal and external environmental factors in the expression of premenstrual symptoms. Preliminary data on efficacy of bright light and sleep deprivation may point to rhythm abnormalities in some women with PMS.

Are There Abnormalities of Menstrually Related Processes in Women with PMS?

Premenstrual symptoms have been shown to be absent during spontaneously anovulatory menstrual cycles.³³ PMS-like symptoms have been reported to be induced in postmenopausal women who received sequential hormonal replacement therapy (HRT), with the cyclic addition of progesterone simulating the cyclic endogenous pattern of progesterone secretion during reproductive age.³⁴ It is likely the case that the postmenopausal induction of symptoms is mostly in women who had PMS in the past. These observations and the cyclicity of symptoms are an indirect suggestion that gonadal hormones and their ovulation-related fluctuations may play a part in the symptoms’ formation of PMS.

The hypothesis that abnormalities of the menstrual-cycle process underlie menstrually related symptoms seems plausible. The “normal” pattern of hormonal changes associated with ovulation of the menstrual cycle is illustrated in the Figure. Hypothalamic gonadotropin-releasing hormone (GnRH) stimulates the anterior pituitary to release follicle-stimulating hormone (FSH) and luteinizing hormone (LH). FSH stimulates the initial secretion of estrogen by the follicles and LH further stimulates follicular development and full secretion of estrogen, triggers ovulation, promotes formation of the corpus luteum, and stimulates the corpus luteum to produce estrogen and progesterone. Moderate levels of estrogen inhibit the release of GnRH and secretion of LH and FSH. High levels of progesterone also inhibit GnRH and LH secretion. High levels of estrogen during the last part of the preovulatory phase can actually exert positive feedback on both the hypothalamus and anterior pituitary gland, resulting in the LH surge that triggers ovulation; this positive effect of estrogen does not occur if progesterone is present at the same time.

Several reports of abnormality in the pattern of estrogen and progesterone secretion have been reported. Among others, pulsatile release of progesterone and LH during the midluteal phase of the menstrual cycle has been described.^35,36 Patients with PMS demonstrate a higher frequency and lower amplitude pulsatile pattern of progesterone secretion, which is temporally related to LH secretion.³⁷ It is of note that the pulsatile release of LH appears to be altered in stress and affective disorders.^37,38 A “zero lag time” between LH and progesterone at symptom onset among PMS patients, suggesting aberrance in corpus luteum response to LH, has also been observed.³⁶ When progesterone and estrogen fluctuated in different rates there was a significant correlation between the difference of rate and severity of symptoms.^39,40 A time lag of 4–6 days between changes of progesterone levels and severity of symptoms implies that hormonal processes in the first half of the luteal phase influence late luteal phase symptoms.^39-41

There are indications that serotonergic abnormalities follow a similar pattern. Serotonergic abnormalities exist on two levels—trait and state.⁴² Women with PMDD may have some abnormal serotonergic (5-HT) processes during the entire cycle (trait) and they may have additional 5-HT abnormalities during the luteal phase (state). The exact cycle time of onset of these processes is currently unknown, but it has been reported that they already exist at the beginning of the luteal phase, at least several days before onset of symptoms, if not earlier.⁴³

The 5-HT abnormalities and their expressions may be related to the fluctuations in activity of gonadal hormones. Gonadal hormones, especially estrogen, interact with many other systems, mostly the reproductive, brain, hormonal, cardiovascular, and other regulatory systems. Therefore, the menstrually related fluctuations induce fluctuation in activity of many systems that may be involved in the formulation of symptoms. Impaired interaction may lead to pathology and disorders. For example, both estrogen and progesterone interact with the renin-angiotensin-aldosterone system (RAAS), which influences electrolyte and fluid balance. Estrogens may stimulate RAAS by inducing the synthesis of angiotensinogen in the liver, thus underlying menstrually related symptoms such as bloating and weight gain.⁴⁴ Progesterone competes with aldosterone at the receptor level, thus exhibiting antimineralocorticoid activity,⁴⁴ and natriuresis is observed during the progesterone-dominated luteal phase of the menstrual cycle.⁴⁵ Therefore, progesterone-mediated effects may favorably impact menstrually related symptoms of bloating and weight gain. Also, decreased CNS corticotrophin-releasing hormone (CRH) secretion in the late luteal and menstruation phases of the menstrual cycle may help to explain increased vulnerability to menstrually related mood disorders such as PMDD.³⁸

Estrogen has been shown to influence multiple CNS processes, including modulation of blood-brain barrier; selective increase of cerebral blood flow; increased supply of glucose and oxygen to neurons; multiple effects on glial cells; regulation of electrolytes’ membrane channels; decreased threshold to seizures and increased excitability; stimulation of dendritic growth and synaptogenesis; differential effects on multiple neurotransmitters; modulation of intraneuronal signal transduction; impact on gene expression; multiple neuroprotection mechanisms; enhanced connectivity and circuitry; and possibly homeostasis.⁴⁶

Among others, estrogen influences some of the major neurotransmitters involved in regulation of mood, behavior and cognitive functions, including serotonin, noradrenaline, GABA, dopamine, and acetylcholine. It also potentiates neuronal excitability. Estrogen has also been shown to be a powerful serotonergic. It increases 5-HT postsynaptic responsivity,⁴⁷ the number of serotonergic receptors, and neurotransmitter transport and uptake.^48,49 Estrogen’s neurostructural effects suggest far-reaching impact on the CNS and human cognitive abilities.⁴⁹ Therefore, luteal increasing and decreasing levels of estrogen have been implicated in PMS symptoms’ formation. However, this assumption is too simplistic because estrogen also increases and decreases during the follicular phase—a period that is mostly asymptomatic. Therefore, additional factors are probably involved.

In direct contrast to estrogen, progesterone appears to have an inhibitory effect on most neuronal activity. For example, progesterone can increase the activity of monoamine oxidase,⁵⁰ whereas estrogen acts as a monoamine oxidase inhibitor, thereby, increasing monoamines’ levels. Progesterone also amplifies the cognitive impairment caused by benzodiazepines, positively interacts with the GABA_A receptor and decreases neuronal excitability. The major reduced progesterone metabolite allopregnanolone has anesthetic and anxiolytic actions. It binds with high affinity to the GABA_A receptor and increases its sensitivity to GABA.⁵¹ The GABA system has been implicated in menstrually related symptoms, such as anxiety, irritability, and premenstrual exacerbation of epilepsy; abnormalities in allopregnanolone synthesis or responsiveness may have a direct involvement in these symptoms.^14,52 In accord with this assumption, levels of allopregnanolone have been reported to be lower in women with PMS during the symptomatic luteal phase as compared to women with no PMS.⁵³

The GABA-related studies raise three practical and heuristically important points. First, not all PMDD symptoms are necessarily related in the serotonergic system. Second, in women with GABA abnormalities, GABAergic treatment may be efficacious also when it is intermittently initiated. This means the patient receives treatment only with the appearance of symptoms, which occur during the late luteal phase. Treatment may be discontinued shortly following the beginning of the next menses with no withdrawal symptoms.^31,32 Therefore, timelines of various abnormalities may differ from each other. Lastly, due to the interaction of the GABA system with progesterone and its metabolites, more sophisticated treatment interventions may be developed.

The diversity of biological processes that may lead to PMS/PMDD may also be demonstrated within the serotonergic system. For example, it has been reported⁴³ that the imipramine receptor binding, but not serotonin uptake, was lower in women with PMS compared to women without PMS during the nonsymptomatic early luteal phase. During the late-luteal phase, which was symptomatic for women with PMS, both groups of women had low levels of imipramine binding. This finding implies that in women with dysphoric PMS, levels of one of the serotonergic variables that usually is putatively associated with dysphoric symptoms did not fluctuate during the luteal phase and was constantly low, while in women with no PMS, levels did fluctuate and became lower premenstrually, even though they did not report any symptoms. These findings suggest that symptom formation may result not only from changes in gonadal hormones, which occur during the early luteal phase, but from abnormal serotonergic activity prior to the symptomatic period as well.

The fact that the imipramine binding of women with no PMS was also low during the premenstrual period may further suggest that for at least some serotonergic functions the significant abnormal process is at the early luteal phase and not in its second half. A recent report²⁸ showed efficacy of the long-acting, once-a-week formulation of fluoxetine when administered twice—at the beginning of the luteal phase and at its middle—but not when given once during the mid luteal phase. This is in accord with our findings.

The peripheral biological abnormalities of women with PMS are probably not limited to the gonads. A case may be constructed to involve the adrenals as well. Adrenal production of dehydroepiandrosterone has been reported to be impaired in women with PMS.⁵³ The adrenals are the peripheral stage in the hypothalamic-pituitary-adrenal (HPA) axis. Regulation of that axis and its feedback mechanisms are probably impaired in some women with dysphoric PMS,⁵⁴ as is the interaction between HPA hormones and gonadal hormones. These aspects may be related to the issue of vulnerability to develop dysphoric PMS. It has been suggested^18,55 that levels of activity of gonadal hormones and their fluctuations are perfectly normal in women with PMS/PMDD (though this assumption is not in accord with all reported data). However these women may be more sensitive to the normal fluctuations and changes, due to increased vulnerability. The nature of that vulnerability has not yet been elucidated.

Pathophysiology of Dysphoric Symptoms Which Are Not Menstrually Related

Underlying mechanisms and similar vulnerabilities may be interpreted from the statistical associations between PMS and some other dysphoric CNS disorders. The association between PMS and anxiety has been demonstrated in American⁵⁶ and European women⁵⁷ and Chinese adolescent girls.⁵⁸ Patients with panic disorder may have 5-HT_1A receptor subsensitivity. Patients with generalized anxiety disorder (GAD) and panic disorder display a decrease in sensitivity to the GABA agonists benzodiazepines, as measured by saccadic eye velocity.⁵⁹ Additionally, the neuropeptide cholecystokinin (CCK) has been shown to increase anxiety in both animals and humans. In addition, patients with panic disorder show an increased number of panic attacks and symptoms when given CCK-4 compared to controls.⁶⁰ This is similar to the CCK-4 effect in women diagnosed with PMDD, suggesting increased sensitivity to this anxiogenic neuropeptide⁶¹ as well as to CO₂ and other stimuli.

The connection between depressions and PMS has been well-studied.^62-65 Alterations in several hormonal and other systems that were found to be abnormal in depressions may be related also to PMS/PMDD including the hypothalamic-pituitary growth hormone, prolactin, and its regulations, hypothalamic-pituitary-thyroid, and especially the HPA-axis that have been extensively noted in depressed patients. The above abnormalities have led to investigations of irregulatory neuropeptides (eg, somatostatin, thyrotropin-releasing hormone, and CRH).

Of special interest for PMDD is the possibility of hypoactivity of the HPA system and changes in glucocorticoids, as well as the interaction between gonadal hormones and the HPA system. The hypoactive HPA system may be involved in the vulnerability to develop PMS/PMDD.

Epilepsy and seizure activity are thought to be the result of an excess of neuronal excitability, with evidence suggesting involvement of alterations in the GABA neurotransmission. Some women with epilepsy have an exacerbation of seizures during the perimenstrual period or periovulatory period in association with progesterone withdrawal and elevated estrogen, respectively. Estrogen inhibits signaling at the GABA receptor while progesterone facilitates this signaling.⁶⁶ The possibility of altered electrical activity in some women with PMS is supported by sporadic reports on the efficacy of anticonvulsants as treatment.

The association between PMS/PMDD and other disorders and the implications for assumption concerning etiology have previously been discussed in more detail.^16,67

Genetics of Premenstrual Symptoms and the Processes of Dynamically Evolving Vulnerability

One of the more intriguing questions concerning PMDD and other reproductive related disorders surrounds the phenomenon that reproductive physiological processes along women’s lifecycle are similar in most women, but only a subgroup of women develop dysphoria during, or in response to these processes.

It is currently well-accepted that vulnerability plays a major role in expression of premenstrual symptoms and syndromes.^18,19,68-70 As is the case with severe life events, such as those that may lead to depression within a few weeks,^71-74 hormonal changes may lead to depression in short period sometimes within days. It is still unclear if increased sensitivity to PMS is genetically determined, is dynamically evolving, or is a combination of both.

The importance of menstrually related processes (presumably hormonal) as triggers to exacerbation of a variety of related disorders has been demonstrated by many researchers. Late luteal phase exacerbation of MDD, bulimia nervosa, epilepsy, panic attacks, agoraphobia, alcoholism, puerperal psychosis-like episodes, periodic psychosis, violent criminal acts, and various other conditions have all been demonstrated.^63,75-85 The diversity of diagnostic entities and symptom clusters that might be expressed during the late luteal phase of the menstrual cycle, suggest that a similar trigger or triggers might cause diversified symptoms, the nature of which depends on the individual’s specific vulnerability.

At present, a strong case for the vulnerability to developing PMDD and other mood related disorders can be made. It is still unknown, however, whether the various biological abnormalities represent distinguishable subgroups of women with different pathways toward the same clinical entity. It is possible that the differing biological vulnerabilities may be associated with diversified syndromal manifestations. In response to the same trigger, women with differing vulnerabilities may develop different symptoms.⁶⁹

The association of genetic propensity to develop PMS and genetic propensity to develop other disorders is still unclear, although statistical association between PMS and several other disorders may lead to the assumption of at least a partial overlap. There may be a particularly strong relationship between PMDD and postpartum depression (PPD).^64,86-88 It is well-documented^62,85,88-94 that there is a high prevalence of lifetime history of MDD, which occurs in 30% to 80% of women with dysphoric PMS or PMDD. Furthermore, women with PMS, especially those with severe dysphoric PMS, are at a higher risk of developing MDD compared to women without PMS.^94,95 Women with dysphoric PMS/PMDD develop anxiety symptoms in response to challenges that induce anxiety and panic symptoms in women with panic disorder. As is case with other symptom clusters, the partial association between PMDD and anxiety disorders may be interpreted as pertaining to a subgroup of women who are vulnerable to such symptoms, through mechanisms revealed by the challenge studies.

The association between dysphoric PMS and social anxiety disorder (SAD) has been suggested,⁹⁶ based on similarity of symptoms and improvement in both in response to light therapy. This was recently demonstrated⁹⁷ by a finding that 46% of women with SAD also make criteria of PMDD, compared to one control with no SAD. Family history and past history of MDD are major risk factors for developing PMDD. Athough they have mostly been studies in the context of PPD, which is suggested to be closely related to PMDD, the same environmental factors that have been suggested as increased risks for depression in general may be suggested to play a role in vulnerability to PMDD as well. Such general environmental vulnerability factors include: premature parental loss,⁹⁸ exposure to pathogenic parental rearing,^99,100 childhood sexual abuse,^101,102 other childhood adversities,^103,104 lack of or deficient social support system,^73,105,106 physical and emotional abuse,¹⁰⁷ recent stressful life events,^{73,106,108-110} and interpersonal difficulties (combinations of lack of parental warmth, social support and recent difficulties—which are related to each other).¹¹¹ Perceived parental warmth decreases vulnerability^112,113 even though familial environment in general probably does not play a major role in vulnerability to depression^111,114,115 or to GAD.¹¹⁶ This is not the case with individual specific environmental risk factors.¹¹¹

The above pathophysiological processes may contribute to a “dynamically evolving vulnerability.”^18,20 That vulnerability may be increased due to early childhood traumatic events or decreased by positive inputs such as perceived parental warmth and strong relatives’ interaction. Accumulation of traumatic experiences might contribute to increased vulnerability even though the interaction here is bi-directional, eg, some people might be more accident prone. This proneness might suggest a genetic determination or contribution of personality or temperament that are also at least partially genetically determined and are influenced by early experiences.^117-120

The dynamically evolving vulnerability is not limited to the past. Environmental inputs at a given state may influence manifestation of symptoms and their severity. It is clinically quite well-observed, though scientifically not strictly documented, that women experience a more severe PMS/PMDD at times of external stress at home or at work. At times of happiness or general relaxation, eg, during a vacation, less severe symptoms or even their absence, is noted.

Suggested Etiology and Its Pathobiologic Components

It has been suggested^15,16,18 that the etiology of premenstrual symptoms is multifaceted and involves several diversified stages. The initial etiological factor is a genetically determined predisposition, which is manifested in propensity to CNS dysregulation and impaired adaptation mechanisms. Hypersensitivity of the individual to changes in gonadal hormones’ activity is a contributing factor to the vulnerability, which may lead to symptoms also during other periods of hormonal change or instability as the postpartum and perimenopause periods. However, the vulnerability to CNS dysregulation and impaired adaptation are not limited to gonadal hormones’ changes; they might be related to impaired adaptation to other situations of change; external stressors as well as abrupt physiological-biological changes, eg, abrupt hormonal withdrawal.

The second stage of genetic vulnerability involves the phenotype predisposition. Different people may be predisposed to phenomena resulting from abnormalities in different CNS systems (eg, 5-HT, noradrenergic, GABA). The genetic vulnerability is constantly being shaped by external and internal environmental inputs. That dynamically evolving vulnerability is probably in progress already during pregnancy and early life and continuously changes according to cumulative negative as well as positive life experiences. Starting with early adolescence, the repeated cyclicity and instability of the hypothalamopituitary gonadal system, especially gonadal hormones and the myriad of processes that are influenced by them, further increase the individual’s vulnerability to disorders. Dynamically evolving vulnerability may increase also due to the kindling effect of repeated dysphoric states.

The cascade of actual PMS symptoms’ formation is triggered by ovulation-related changes in gonadal hormones, mostly those occurring during the luteal phase. These changes influence multiple CNS and peripheral systems and processes. In women with high dynamically-evolving vulnerability, dysregulation occurs and symptoms appear. The occurrence of symptoms and their severity depends on the environment at a given state. Perception of symptoms and ability to cope with them is also individualistic and is shaped by past experiences as well as constellation of several CNS systems.

The etiology pathways of PMS are genetic predisposition to PMS (and other relations situations)/phenotype predisposition, dynamically evolving vulnerability, current luteal phase changes in gonadal hormones, environment at a given state, and perception and coping mechanisms.¹⁶

Conclusion

The involvement of numerous and diverse premenstrual phenomena related to the brain and to peripheral body systems should be further assessed. The large number of systems that have been found to be abnormal in women with PMS may point to diversified biological subgroups and disrupted homeostasis among the systems involved. Vulnerability to external and internal stimuli is increased during periods of change or alteration in one or in several components or systems. At these time periods, a relatively minor stressor may trigger in severe symptoms. The realization that any symptom may be presented as PMS should lead to the elucidation of the diversified biological vulnerabilities and diversified treatment modalities aimed at subgroups of women with PMS who have the specific phenotype and/or vulnerability.

Although it is accepted that ovulation-related mechanisms trigger PMS in vulnerable women, the exact process remains unknown. It is not clear if the culprits are post-ovulatory gonadal hormones, their metabolites, or even processes leading to ovulation. Further research and an open-minded approach are needed to pinpoint triggers, maximize treatment efficacy, and develop more advanced conceptualizations of etiology and pathobiology. PP

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Dr. Halbreich is professor of psychiatry and OB/GYN and director of Biobehavioral Research at the State University of New York at Buffalo.

Mr. Monacelli is research assistant in the Biobehavioral Program at the State University of New York at Buffalo.

Disclosure: Dr. Halbreich has received financial support from Berlex, Bristol-Myers Squibb, Eli Lilly, and Pfizer. Mr. Monacelli reports no financial, academic, or other support that may pose a conflict of interest.

Acknowledgments: The assistance of Sandhya Karkun is greatly appreciated. This work is mostly based on four recent publications noted in the Introduction section of this article.

Please direct all correspondence to: Uriel Halbreich, MD, Director of Biobehavioral Research State University of New York at Buffalo, Hayes Annex “C”, Suite 1, 3435 Main St, Buffalo, NY 14214; Tel: 716-829-3808; Fax: 716-829-3812; E-mail: urielh@buffalo.edu.