Hormonal responses to the administration of m-chlorophenylpiperazine in patients with seasonal affective disorder and controls

Hormonal Responses to the Administration of m-Chlorophenylpiperazine in Patients with Seasonal Affective Disorder and Controls Diego Garcia-Borreguero, Frederick M. Jacobsen, Dennis L. Murphy, Jean R. Joseph-Vanderpool, Alexandra Chiara, and Norman E. Rosenthal

We report on the plasma cortisol and prolactin responses to the serotonergic agonist m-CPP (0. l mg/kg) in 10 patients with winter seasonal affective disorder (SAD) and 10 controls during the winter, in both untreated and bright light-treated conditions; and on 8 other SAD patients and 8 other controls during the summer. Following m-CPP infusion, untreated patients had exaggerated prolactin (p < . 05) and cortisol (p < .05) responses compared to controls. Light treatment significantly reduced responses of both hormones to m-CPP (prolactin: p < .01; cortisol: p < .01). When untreated winter subjects and summer subjects were compared, cortisol, but not prolactin responses to m-CPP were found to be higher in patients than in controls during the winter, and lower in patients than in controls during the summer (diagnosis by season: p < .05). These results are consistent with those of our previous report on the behavioral responses to m-CPP in the same patients and suggest an abnormali~ in serotonergic function in untreated SAD patients in winter, which is normalized following treatment with light therapy and naturally during the summer.

Key Words: Seasonal affective disorder (SAD), m-chlorophenylpiperazine (m-CPP); serotonin, light therapy, prolactin, cortisol

Introduction Several lines of evidence implicate serotonin (5-HT) systems in the pathophysiology of seasonal affective disorder (SAD) and the antidepressant effects of light therapy: First, there is marked seasonal variation in many biological parameters related to serotonin metabolism in humans (Lacoste and Wirz-Justice 1989; Brewerton 1989). Second, From the National Institute of Mental Health, Clinical Psychobiology Branch, Laboratory of Clinical Science, Bethesda, MD. Please address reprint requests to Normal E. Rosenthal, M.D.. National Institute of Mental Health, Clinical Psychobiology Branch, Bldg. 10, Room 4S-239, 9000 Rockville Pike, Bethesda, MD 20892; Fax: (301 ) 496-5439. Received February 2, 1994; revised July 29.1994.

© 1995 Society of Biological Psychiatry

both d-fenfluramine, a serotonergic releasing agent, and fluoxetine, a selective serotonin reuptake inhibitor (SSRI), have been reported to be effective in treating SAD patients (O'Rourke et al 1989: Kasper et al 1993). Third, there is a physiological relationship between dietary carbohydrate intake, which is reportedly increased in SAD patients (Rosenthal et al 1984), and brain serotonin systems. Specifically, high-carbohydrate meals have been shown to increase the ratio of plasma tryptophan (a precursor of serotonin) to other large neutral amino acids (Fernstrom and Wurtman 1971). SAD patients report feeling activated after such meals, whereas control subjects report feeling sedated (Rosenthal et al i 989). Since dietary carbohydrate is believed to 0006-3223/95/$09.50 SSDI 0006-3223(94)00208-K

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enhance serotonin synthesis and transmission (Wurtman and Wurtman 1989), the carbohydrate craving typical of patients with SAD has been hypothesized to reflect a behavioral attempt to compensate for a putative serotonergic deftciency (Rosenthal et al 1989). Finally, neurophysiological studies in rats have shown that light stimulates the firing of serotonergic neurons (Mason 1986; McNulty et al 1986; Fraikin et al 1989; Azuma et al 1991; Cagampang et al 1993), and direct neural connections between the retina and the raphe nuclei (the main source of brain serotonin) have been described (Foote et a11978). The technique of challenging brain receptors by pharmacological probes and measuring the resulting hormonal output is a well-established strategy for investigating putative neurotransmitter system abnormalities in psychiatric conditions (Freedman 1987). Serotonergic neurons send collaterals to limbic and neuroendocrine areas of the brain. Thus, hormones that are released by serotonergic neurons might be used as a measure of serotonergic involvement in emotional disorders. This strategy has been employed in the investigation of brain serotonergic systems in multiple psychiatric conditions, including mood disorders in general (Murphy et al 1986; van Praag et al 1987; van de Kar 1991) and SAD in particular (Jacobsen et al, 1987). In the latter study, we used the 5-hydroxytryptophan to probe the serotonergic system in SAD patients and controls and found no difference in the induced cortisol and prolactin responses. In the present study, we have used a probe that is more selective for brain serotonergic systems. Meta-chlorophenylpiperazine (m-CPP), a serotonergic agonist partially selective for the serotonergic 5-HT2c (previously known as 5-HTlc receptor (Humphrey et al 1993)), has been used extensively in animal and human studies (Mueller et al 1985; Kahn and Wetzler 1991). We have previously reported on the behavioral responses to administration of rn-CPP in treated and untreated SAD patients and controls in winter (Jacobsen et al 1994) and in separate groups of SAD patients and controls in the summer (Joseph-Vanderpool et al 1993). In the present paper we report on the hormonal responses to m-CPP during both the winter and the summer in the same SAD patients and controls during the same studies that formed the basis of the earlier reports.

Methods Subjects and Study Design Ten patients (7 females and 3 males) who met criteria for seasonal affective disorder (Rosenthal et al 1984) and 10 normal controls matched for age, gender, weight, and menstrual status (5 premenopausal, 2 postmenopausal) underwent a 1- week period without any treatment ("off-lights") followed by a 1-week period of light therapy consisting of 4

hours of 2500 lux white light per day ("on-lights"). Light therapy was administered for 2 hours between 6:30 AM and 9:00 AM and for another 2 hours between 5:00 PM and 9:00 PM. At the end of each period, an infusion of m-CPP was administered in the morning. Similar infusions were administered to 8 different SAD patients (4 women and 4 men; 2 premenopausal, 2 postmenopausal) and 9 different matched controls (5 women and 4 men) during the summer (July 1989). Subjects participating in the summer study were chosen so that they resembled the demographic profile of those studied during the previous winter. All patients participating in the summer study met diagnostic criteria of Rosenthal et al. (1984) for seasonal affective disorder and for lifetime history of major depression with seasonal pattern, as defined by DSM-III-R (American Psychiatric Association 1987). The mean age of the patients and controls was 40.1 _+ 7.9 (SD) and 41.3 _+ 9.3 years, respectively, in the winter study and 39.3 _+ 9.1 for patients and 37 -+ 8.7 for controls in the summer study. During the winter study, no subject took psychotropic medication for at least 3 weeks before the study; all had abstained from other drugs and alcohol for at least 1 week before the study. Except for one SAD patient, no subject had previous exposure to light therapy. In the summer study, all subjects had been medication free for at least 4 weeks before the study (Jacobsen FM et al 1994; Joscph-Vanderpool et al 1993). A history of migraine headaches was regarded as an exclusion criterion, since m-CPP has been reported to trigger migraines in vulnerable individuals (Brewerton et al 1988). We should note that one male patient included in the earlier behavioral study of Jacobsen et al (1994) was not available for inclusion in the present study because it was not possible to obtain blood samples from him.

m-CPP Stimulation Test and Hormone Assays On each study day, two intravenous (IV) lines were inserted, one into each forearm; 10:00 AM, m-CPP was administered at a dosage of 0.1 mg/kg over 90 seconds through one of the IV lines, m-CPP was obtained from Aldrich Pharmaceutical Co (Milwaukee, Wisconsin) and was prepared by the NIH Pharmaceutical Developmental Service. To avoid contamination of the plasma levels of m-CPP by residual drug in the IV line after the infusion, blood was drawn through an IV line on the other arm. Blood specimens for measurement of plasma levels of prolactin and cortisol were drawn at baseline and at 10 (only in the summer study), 20, 30, 40, 50, 60, and 90 minutes after the administration of m-CPP. Samples for prolactin and cortisol were collected in heparinized tubes and stored at -30°C. The prolactin assay had a detection limit of 2 ng/ml, with intra-assay coefficients of variation of 11.0%, 6.8%, and 7.2% for low, mid, and high controls, respectively, and interassay coefficients of variation of 11.0%, 8.0%, and 9.4% for means of 3.9, 15.7, and

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43.0 ng/ml, respectively (Sinha et al 1973). The cortisol assay had a detection limit of 0.3-0.7 ~g/dl, with intra-assay coefficients of variation of 5.2% and 5.8% and interassay coefficients of variation of 12.2 and 11.1% for means of 6.3 and 6.3 p.g/dl, respectively (Abraham et al 1972).

Rating Scales Severity of depression was rated at the end of each treatment period by blind raters, who administered the 21-item Hamilton Depressive Rating Scale (HDRS; Hamilton 1967) along with seven atypical depressive items (Rosenthal and Hefferman 1986). The behavioral response to m-CPP was assessed by means of the the 24-item National Institute of Mental Health (NIMH) self-rating scale (Murphy et al 1989). Subjects were asked to complete the 24-item NIMH self-rating scale at baseline, and at 30, 60, and 90 minutes after m-CPP was infused. Six subscale scores were compiled from the 24item NIMH scale as previously described: "activation/ euphoria," "depression," "anxiety," "altered self awareness," "functional deficit," and "dysphoria" (van Kammen et al 1975; Murphy et al 1989). The "activation-euphoria" subscale, which includes the items "I feel energetic," "I feel elated," "I feel talkative," and "I feel racing thoughts," has previously been shown to differentiate untreated SAD patients from normal controls following m-CPP administration (see Jacobsen FM et al 1994; Joseph-Vanderpool et al 1993). Subjects were asked to rate the following side effects on a four-point scale: "slowed down," "drowsy/sleepy," "chilled," "lightheaded/dizzy," "trouble remembering/ concentrating," "yawning," "hot/flushed feeling," "visual changes," "nausea," and "headache" (Joseph-Vanderpool et a11993; Jacobsen FM et al 1994).

Statistical Analysis The baseline values for the plasma levels of each hormone across treatment conditions in the winter (winter "offlights" vs winter "on-lights") were analyzed by means of an analysis of variance (ANOVA) containing one grouping factor (diagnosis) and one repeated measure (light condition). The baseline values across seasons (winter "offlights" vs summer) were analyzed by an ANOVA containing two between variables (diagnosis, season). Effects of the administration of m-CPP on subsequent hormonal plasma levels across treatment conditions in the winter were assessed by means of ANOVA with repeated measures, with one grouping factor (diagnosis) and two repeated measures (light condition, time). Huynh-Feldt corrections were used in these cases where the data did not meet the assumption of sphericity (Huynh and Feldt 1980). The hormonal effects of m-CPP

across seasons were analyzed by an ANOVA with repeated measures containing two grouping factors (diagnosis and season) and one repeated measure (time). To rule out the possible influence of baseline differences, the ANOVA was performed on change-scores (each value minus baseline value). Since we had found exaggerated responses on the NIMH self-rating behavioral subscale "activation-euphoria" in the same untreated SAD patients during the winter--responses which were normalized both after light therapy and during the summer (Joseph-Vanderpool et al 1993; Jacobsen FM et al in press, 1994)-we explored a possible association between hormonal responses to m-CPP and behavioral responses on the "activation-euphoria" subscale in SAD patients. To do so we performed linear regressions between the areas under the plasma concentration response curve (AUC) of each hormone on each condition and the AUC of the activation-euphoria response curve to m-CPP (JosephVanderpool et al 1993) on each condition in the patient group. In addition, we evaluated whether hormonal responses were a function of severity of depression in the untreated, "off-lights" condition in SAD patients by performing regressions between the AUC of the hormone response curves and the typical and atypical scores on the Structured Interview Guide for the Hamilton Depression Rating Scale-Seasonal Affective Disorder Version (SIGHSAD). Statistical analysis and data representation were performed using the programs Statview and SuperAnova.

Results Baseline Values Before and After Light Therapy in Winter, and in Summer HAMILTON DEPRESSION RATINGS. Before light therapy, patients with SAD had mean - SEM baseline HDRS scores of 17.3 -+ 1.2 and atypical depression scores of 14 +_ 1.5. After 1 week of light therapy, corresponding scores were 7.9 +_ 1.4 and 2.9 - 0.6. HDRS scores for SAD patients studied during the summer were 3.25 _+ 3.9, and atypical scores were 1.0 _+ 1.1 (Joseph-Vanderpool et al 1993).

HORMONE VALUES. Table 1 shows the baseline average values ( + SEM) of prolactin and cortisol in both groups. ANOVA did not show any significant main effects or interactions for either hormone. PHYSICAL SYMPTOMS SCALE. During the winter, the only baseline differences between patients and normals on the 11-item drug-effect form were "memory," "slowed down," and "drowsy," in which SAD patients were more handicapped than normals (Jacobsen FM et a11994).

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Table 1. Average Plasma Levels (___SEM) of Prolactin and Cortisol at Baseline Prolactin

Cortisol

Winter

Patients Controls

Summer Treated

Untreated

Untreated

Treated

Untreated

7.35 (+_0.67) 8.41 (+-0.87)

731 (_+0.69) 9.56 (_+1.43)

6.51 (_+1.52) 6.63 (_+0.80)

8.73 (-+ 1.28) 6.02 (_+1.03)

9.58 (-+ 1.44) 5.68 (_+0.85)

9.09 (+ 1.05) 9.36 (_+0.67)

COMPARISON BETWEEN PATIENTS AND CONTROLS DURING SUMMER. There were no statistically significant differences between patients and controls in the prolactin response to m-CPP during the summer (Figure lb).

COMPARISON BETWEEN "OFF-LIGHTS" AND "ONLIGHTS" CONDITIONS IN WINTER. A N O V A showed significant main effects for diagnosis (F = 5.66; df = 1,18; p < .05) and light treatment condition (F = 8 . 7 1 ; df = 1,18; p < .01) but no significant interactions. As Figure l a and Table 2 indicate, the prolactin responses were higher in patients than in normals and for both groups in untreated as compared with light-treated conditions.

COMPARISON BETWEEN THE OFF LIGHTS CONDITION ACROSS SEASONS. Although prolactin responses appear higher in untreated patients in winter as compared with summer (Figure 1), these differences did not reach statistical significance (Table 3). There were no significant interactions resulting from this ANOVA.

(b)

WINTER: UNTREATED VS. LIGHT TREATED

WINTER UNTREATED VS. SUMMER

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Figure 1. Baseline corrected plasma levels ofprolactin.

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Table 2. Results of ANOVA on Hormonal Responses to m-CPP during Winter Winter off Lights vs. Winter on Lights Co~isol

Prolactin

Diagnosis Light condition Diagnosis * light condition Time Time * diagnosis Time * Light condition Time * diagnosis * Light condition

df

F

p

df

F

p

l, 18 l, 18 1,18 5,90 5,90 5,90 5,90

5.665 8.712 0.243 1.425 2.227 1.754 0.648

* ** NS NS NS NS NS

1,18 l,l 8 1,18 5,90 5,90 5,90 5,90

8.078 13.065 0.267 16.791 1.071 2.334 1.506

* ** NS * ** NS NS NS

ANOVA = analysisofvariance; m-CPP = meta-chlorophenylpiperazine; NS = notsignificant. *p <.05. **p < .01. ***p <.001. #p =.09.

Cortisol: Baseline Corrected Values Following m- CPP Infusions COMPARISON

BETWEEN

"OFF-LIGHTS"

LIGHTS" CONDITIONS IN WINTER.

ANOVA

AND

"ON-

s h o w e d sig-

nificant main effects for diagnosis (F = 8.08, df= 1,18; p < .05), light treatment condition (F = 13.06; df= 1,18;p < .01 ) and time (F = 16.79; df= 5,90;p < .001) but no significant interactions (Table 2). As Figure 2a and Table 2 indicate, the cortisol responses to m-CPP are higher in SAD patients than in controls and in off- versus on-light conditions. COMPARISON BETWEEN

PATIENTS AND CONTROLS

There were no statistically significant differences between patients and controls in the cortisol response to m-CPP during the summer (Figure 2b). DURING THE SUMMER.

significant. As Figure 2 indicates, patients showed a higher cortisol response than controls during the winter, but a lower response than controls during the summer. CORRELATIONS BETWEEN THE H O R M O N A L AND BE-

No statistically significant correlations were found between the areas under the curve (AUC) of the prolactin and cortisol responses to m-CPP in the "off-lights" condition. Similarly, no statistically significant associations were found between the AUC of either of the hormonal responses to m-CPP and the AUC of the "activation/euphoria" behavioral subscore. Furthermore, there were no significant correlations between the changes in the AUC for these variables across light treatment conditions. HAVIORAL RESPONSES TO m-CPP IN THE SAD GROUP.

RELATIONSHIP

BETWEEN

SEVERITY

OF

ILLNESS/

COMPARISON BETWEEN THE "OFF-LIGHTS" CONDI-

ANTIDEPRESSANT RESPONSE TO LIGHT THERAPY AND

A N O V A showed a statistically significant main effect for time (F = 3.32; df= 5,160; p < .05), and significant interactions for diagnosis x season (F = 4,5; df= 1,32; p < .05), and season x time (F = 2.78; df= 5,160; p < .05) (Table 3). Other interactions were not

HORMONAL RESPONSES TO m-CPP IN THE SAD GROUP.

TION ACROSS SEASONS.

There were no significant correlations between severity of illness (as measured by HDRS or Atypical symptom scores) and hormonal responses to m-CPP nor between the change scores for these variables across treatment conditions.

Table 3. Results of ANOVA on Hormonal Responses to m-CPP Across Seasons Winter off lights vs. S u m m e r Prolactin

Diagnosis Season Diagnosis * season Time T i m e . diagnosis Time * season Time * diagnosis * season

Cortisol

df

F

p

df

F

p

1,32 1,32 1,32 5,160 5,160 5,160 5,160

0.312 0.629 2.495 0.489 0.818 1.497 0.184

NS NS NS NS NS NS NS

1,32 1,32 1,32 5,160 5,160 5,160 5,160

0.951 2.186 4.501 3.323 1.574 2.781 1.371

NS NS * * NS * NS

ANOVA = analysis of variance;m-CPP = meta-chlorophenylpiperazine; NS = not significant. *p < .05.

Hormonal Responses to m-CPP in SAD Patients and Controls

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Figure 2. Baseline corrected plasma levels of cortisol. (a) Winter treated vs. untreated. (b) Comparison of both groups across seasons. m-CPP

PLASMA

LEVELS

AFTER

DRUG

ADMINISTRA-

There were no significant differences in m-CPP plasma levels across diagnostic groups or treatment conditions in the winter. No plasma levels for m-CPP were available for the summer study (Joseph-Vanderpool et al 1993). No migraines were induced by m-CPP in any of the studies. TION.

Comment In the present study we found increased prolactin and cortisol response to the mixed serotonergic agonist m-CPP in untreated SAD patients compared to healthy controls during the winter. Prolactin and cortisol responses decreased after treatment with light therapy in both groups. When the hormonal responses to m-CPP of patients and controls were compared with two separate groups of SAD patients and controls studied during the summer, the seasonal effects on cortisol response were different across groups. Specifically, cortisol response was significantly diminished in patients, but increased in controls during the summer. No differences were found in the prolactin response to m-CPP across seasons. As we have pointed out in our previous paper describing the behavioral responses to m-CPP of these same patients

(Joseph-Vanderpool et al 1993), the present study has four main limitations: First, different subjects were studied during the two seasons. A within-subjects design might have decreased the variance between seasons, thereby increasing differences across seasons. Unfortunately, such a design was not possible due to subject unavailability. Second, there was no placebo control. The observed differences might thus be attributed to a nonspecific response in SAD patients to the administration of the drug. However, more recent evidence from a placebo-controlled study on 17 SAD patients suggests that both cortisol and prolactin responses to placebo were no different in patients and controls, suggesting that SAD patients do not respond differently to the nonspecific aspects of having an intravenous procedure (Rosenthal NE, Garcia Borreguero D, Schwartz P, Oren DA, Ozaki N, Moul DE, Snelbaker A J, Murphy DL, unpublished observation, 1993). Third, no plasma levels were obtained for m-CPP during the summer; however, there were no differences in m-CPP plasma levels between patients and controls during the winter. Thus, there is no reason to believe that there would be any between-group differences in m-CPP blood levels during the summer. Fourth, there was a fixed order of presentation of treatment condition, which might have allowed order effects to occur.

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Future studies should incorporate placebo-controlled designs, as well as a randomized order of treatment. The exaggerated prolactin and cortisol responses to mCPP in untreated SAD patients are reminiscent of the exaggerated "activation-euphoria" responses to m-CPP that we reported previously in the same subjects. The partial normalization of prolactin and cortisol responses in patients following light therapy is also reminiscent of the normalization of the behavioral responses that occurred in these circumstances. The same could be said for the partial normalization of cortisol responses in patients in summer. We have subsequently replicated the behavioral findings in a separate study. In this second study, the hormonal responses were only partially replicated (Rosenthal NE, Garcia-Borreguero D, Schwartz PJ, Oren DA, Ozaki N, Moul DE, Snelbaker AJ, Murphy DL, unpublished observation, 1993). Specifically, the lowering of prolactin response following light therapy was once again observed, as was a significant group by light treatment condition effect in cortisol response. The nature of the light treatment × group interaction in the second study, however, was somewhat different and more complicated. In addition, in the second study, adrenocorticotropic hormone (ACTH) levels were measured and found to be blunted in untreated SAD patients, a blunting which was increased to normal levels following light therapy. It would seem paradoxical that cortisol responses to m-CPP in SAD patients were exaggerated in the present study whereas ACTH responses to the same drug were blunted in the second study. In attempting to reconcile these findings, we should note that there were certain methodological differences between these two studies, in particular the dose of m-CPP used (0.08 mg/kg in the second study vs. 0.1 mg/kg in the present study). We interpreted our earlier behavioral findings to reflect supersensitivity of serotonin receptors in untreated SAD patients in the winter, secondary to reduced serotonin availability. The hormonal findings in the present study could be explained by the same hypothesis. Insofar as the release of both prolactin and cortisol are stimulated by serotonin, the exaggerated prolactin and cortisol responses seen in untreated SAD patients could be viewed as a function of supersensitive serotonin receptors. The reduced hormonal responses following light therapy and in summer might result from increased serotonin availability with desensitization of serotonin receptors. This hypothesis is supported by documented seasonal rhythms in a variety of serotonin subsystems (Lacoste and Wirz-Justice 1989; Brewerton 1989). Postmortem studies of healthy controls have shown hypothalamic levels of serotonin to be at their lowest during the winter months (Carlsson et al 1980). Patients with SAD may experience an exaggeration of this normal tendency or may be more vulnerable to normal seasonal variations. Besides the above-mentioned changes in hypothalamic

serotonin content (Carlsson et al 1980), other parameters of serotonergic function have also been found to have seasonal variations in healthy humans. These include: CSF 5-HIAA, platelet 5-HT, platelet 3H-imipramine binding, free- and total plasma tryptophan, and plasma 5-HT (for review, see Brewerton 1989). In the present study, we detected no baseline differences in either plasma prolactin or cortisol. Previous studies have been inconsistent with respect to seasonal variations in plasma prolactin (Lacoste and Wirz-Justice 1989), with some studies reporting higher plasma prolactin levels in women in spring and summer and lower levels in fall and winter (Bellacastella et al 1983; Touitou et al 1983; Brown et al 1988), and others finding no seasonal variations in plasma prolactin (Guagnano et al 1984; Martikainen et al 1985; Kivela et al 1988; Depue et al 1989). In contrast, plasma cortisol levels have been found to be consistently higher in the winter months (Lacoste and Wirz-Justice 1989; Rybakowski and Plocka 1992; Kathol 1985; Agrimonti et al 1982; Reinberg 1978; Watanabe 1964; Halberg et al 1965). Plasma prolactin responses to L-tryptophan and m-CPP have been shown to vary seasonally, with more pronounced responses occurring in fall and winter (Brewerton, 1989). This finding is consistent with those of the present study and with the hypothesis that serotonin receptors may be supersensitive in the winter, secondary to decreased synaptic serotonin availability. Plasma prolactin and cortisol responses have also been evaluated in other psychiatric conditions. In patients with obsessive-compulsive disorder, prolactin, but not cortisol, responses to 0.1 mg/kg m-CPP IV have been found to be blunted (Charney et al 1988). In contrast to this, the response of both hormones to IV administration of m-CPP 0.1 mg/kg has been found to be normal in panic disorder (Charney et al 1987), schizophrenia (Seibyl et al 1989; Owen et al 1993), and Alzheimer's disease (Lawlor et al 1989). As suggested above, the present findings may reflect an overall deficiency of serotonin available at the synapse, with resulting postsynaptic receptor supersensitivity. This abnormality may be reflected by the agonist properties of m-CPP, which has been shown to bind potently to several kinds of 5-HT receptor types in vitro, most particularly 5-HTla, 5-HTlb, 5-HT2a, 5-HT2c, and 5-HT3 receptors (Hamik and Peroutka 1989; Hoyer 1988; Murphy et al 1991). Among these, it has greatest affinity for the 5-HT2c receptor, where it exerts agonist effects. The cortisol secretory response to m-CPP's is probably mediated by 5-HT2c receptors, since the ACTH release can be partially antagonized by ritanserin (a 5-HT2a/5-HT2c antagonist) and metergoline (an antagonist of 5HT1/5HT2 receptors) but not by the 5HT2a receptor antagonist ketanserin (Seibyl et a11989; Badgy et a11989). Although serotonin receptors have been described on the adrenal gland itself

Hormonal Responses to m-CPP in SAD Patients and Controls

(Alper 1990; Delarue et al 1988), the stimulatory effects of m-CPP on cortisol appear to be mediated centrally via stimulation on corticotropin-releasing hormone (CRH) and ACTH, since either the administration of dexamethasone or anti-CRH rabbit antiserum suppresses on m - C P P induced cortisol release (Calogero et al 1990; Murphy et al 1991). The prolactin-releasing effects of m-CPP appear to be mediated mainly by 5-HT2c receptors in animals (Aulakh et al 1992; Jcrgensen et al 1992). Direct data on the association of m-CPP with the stimulation of a particular 5-HT receptor in humans are limited so far to studies that showed an attenuation of the m-CPP-induced release of prolactin and cortisol after pretreatment with the mixed 5HT2a/2c receptor antagonist ritanserin (Seibyl et al 1989) and the 5 - H T l / 2 antagonist metergoline (Mueller et al 1986), suggesting by elimination a primary involvement of 5-HT2c receptors in m-CPP-induced release of

BIOL PSYCHIATRY 1995:37:740-749

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prolactin and cortisoi, since m-CPP is an antagonist at 5-HT2a and 5-HT3 receptors. As with the aberrant responses to m-CPP previously published (Joseph-Vanderpool 1993), the hormonal responses to m-CPP reported here might represent a state marker for winter depression and further implicate brain serotonergic abnormalities in the pathophysiology of SAD. While the preponderance of evidence suggests a deficiency in serotonin availability, it is also possible that these aberrant responses in S A D patients reflect receptor or postreceptor factors. Further studies using different presynaptic and postsynaptic challenges might clarify which of these explanations is most plausible.

We acknowledgeTerry Tolliver for her technical assistance in measuring the m-CPP plasma levels.

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