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Seasonal variation in behavioral responses to m-CPP in patients with seasonal affective disorder and controls
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Seasonal Variation in Behavioral Responses to m-CPP in Patients with Seasonal Affective Disorder and Controls Jean R. Joseph-Vanderpool, Frederick M. Jacobsen, Dennis L. Murphy, James L. Hill, and Norman E. Rosenthal
Thts paper reports the behavioral responses to m-chlorophenylpib~erazine (m-CPP), a serotonin agonist, in patients with seasonal affective disorder (SAD) and controls during the summer. Results are compared with the responses of SAD patients and controls given m-CPP in the winter. Results of the winter study were reported earlier by our group. Baseline Hamilton depression ratings in SAD patients were significantly lower in the summer than in winter (p < 0.05). Additionally, in both SAD patients and controls, there were seasonal differences on the National Institute of Mental Health (NIMH ) self-rating scale items: "depressed affect," "dysphoria," and "functional deficit" at baseline. The behavioral responses to m-CPP across seasons differentiated patients from normals only in the "activation~euphoria'" item, on which afar greater response was seen in patients than in controls during the winter. This behavioral response may be a state marker for winter depression, as it was significantly reduced after light treatment of these patients in the winter, and in the summer, SAD patients responded differently from4controls on "altered self-awareness" and "dysphoria " independently of seasons, and these responses may be considered as possible trait markers for this condition. These results provide further evidence of a possible deficiency in serotonergic trattemis~ion in seasonal affective disorder.
Key Words: Seasonal affective disorder, seasons, light, serotonin, depression, circadian rhythms
Introduction Winter seasonal aff,.ctive disorder (SAD) is characterized by recurrent winter depressions alternating with nonde-
the Section on Environmental Psychiatry. Clinical Psychobiology Branch, NIMH, Bethesda,/riD. Address reprmt requests to Norman E. Roseothal, MD, Chief, Section on Environmental Psychiatry, Clinical Psychobiology Branch, NIMH, Bid. 10 Rm 4S/239, 9000 Rockville Pike, Bethesda, MD 20892. Received March 31. 1992; revised November20, 1992. From
© 1993 Society of Biological Psychiatry
pressed periods in spring and summer (Rosenthal c~ al 1984). During the winter, SAD patients often gain weight, crave carbohydrates, oversleep, and are lethargic. In contrast, they often lose weight, sleep less, and are more energetic in the summer when their depressions remit. Because several of the above behaviors are thought to be modulated by brain serotonin systems (Meltzer 1990; Curzon 1990; Jimerson et al 1990), a dysregulation of serotonergic transmission has been postulated in SAD (Rosenthal et al i984; Jacobsen et al 1989). 0006-3223/93/$06.00
Behavioral Responses to m-CPPP in SAD
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Speculation about serotonergic disturbances in SAD stems from several pieces of information: First, there is extensive evidence of seasonal variations in serotonergic systems in humans (Lacoste and Wirz-Justice 1989). Second, d-fenfluramine, a serotonin agonist, has been found to be effective in treating SAD patients (O'Rourke et al 1989). Third, SAD patients report feeling more activated following a high-carbohydrate meal compared to controls, who report feeling more sedated (Rosenthal et ai 1989). Because dietary carbohydrate intake is thought to affect brain serotonin synthesis and transmission (Fernstrom and Wurtman 1971; Wurtman and Wurtman 1989), this aberrant response may reflect serotonergic dysregulation. In addition, carbohydrate craving and increased carbohydrate intake, which are characteristic winter symptoms in SAD patients, may reflect a behavioral attempt to normalize this putative serotonergic abnormality (Rosenthal et al 1984). Finally, depressed SAD patients have reported increased activation and euphoria following intravenous infusions of the serotonergic agonist, m-CPP, during the winter, and these behavioral responses to m-CPP ~.~fusions we.re ~ttenanted and no.-malized after light therapy Oacebsen et al 1989). In order to determine whether the atypical behavioral responses of SAD patients to m-CPP are a reflection of their winter depressed state or a possible trait marker for SAD, we repeated the m-CPP infusion paradigm in a new group of euthymic SAD patients and a group of normal controls during the summer. We report here on the findings of this study and compare the new results with the findings of our earlier winter study.
Materials and Methods Subjects
Subjects who participated in the summer study were eight SAD patients, (four women and four men) and nine controis (five women and four men). Mean age ( ± SD) of SAD patients was 39.3 -+ 9. !, and of the controls was 37 _+ 8.7. All subjects were outpatient ; during the course of the study, and all gave informed voluntary written consent for their participation. The groups were chosen so that they resembled in demographic profile those studied previously by our group in the winter. Thus, in the earlier winter study there were l0 patients (7 women and 3 men) and l I controls (8 women and 3 men), whose mean ages ( ± SD) were 40 ± 7.9 and 41 ± 9.3 years, respectively. For the control group we selected women of similar menstrual status to those in the patient group. All patients met diagnostic criteria of Rosenthal et al (1984) tor seasonal affective disorder and i'ur major depression with seasonal pattern, as defined by the Diagnostic and Statistical Manual for Psychiatric Disorder (DSM-III-
R) (American Psychiatric Association 1987). None of the controls had any history of psychiatric disorders, as determined by Structured Clinical Interview for DSM-III-R (SCID) (Spitzer et al 1986). All subjects underwent routine physical examinations and laboratory tests before the study. Botch patients and controls were medically healthy and medication free for at least 4 weeks before the study. Patients were rated by trained blind raters, who administered the 21-item Hamilton Depressive Rating Scale (HDRS) (Hamilton 1967) along with seven atypical depressive items that have been shown to have particular relevance to SAD (Rosenthal and Heffernan 1986). Procedures
Following an overnight fast, indwelling venous catheters were inserted into forearm veins of both arms at 8:30 Arvl and kept patent with hepadnized normal saline solution. Subjects were instructed to sit in reclining chairs and were permitted to read, knit, watch television, or perform desk work dufiq~ the course of the study. After insertion of the IV, subjects were adapted to the experimental conditions until 9:50 AM. They were then asked to complete a series of rating forms including the NIMH 24-item self-rating scale (Van Kammen and Murphy 1975; Murphy et al 1989) as well as the appended items, ("have suicidal thoughts," "have repetitive thoughts," and "feel like eating sweets/starches"), the Stanford Sleepiness Scale (Hoddes et al 1973), and 10 drug-effect items. Drug-effect items were rated on a fourpoint scale (none, slight, moderate, much) and included the items "slowed down," "drowsy/sleepy," "chilled," "lightheaded/dizzy," "trouble remembering/concentrating," "yawning," "hot/flushed feeling," "visual changes," "nauseated," and "headache." The two other items, "vomiting" and "penile erection" were rated either "Yes" or "No." Six subscale scores were compiled from the NIMH 24-item scale as previously described: "activation/euphoria," "depressed atlect,-~ . . . . . . . zmxie a,t~,.u o,,,-a . . . . . . . . . "functional deficit," and "dysphoria" (Van Kammen and Murphy 1975; Murphy et al 1989). Subjects were given m-CPP, 0.1 mg/kg IV over 90 sec at 10 AM (0 min) after the first battery of ratings scales had been completed. Administration of rating sca!es was repeated at 30, 60, and 90 min after m-CPP was infused. The investigators obtained m-CPP from Aldrich Pharmaceutical Co (Milwaukee, WI) and it was prepared by the National Institutes of Health (NIH) Pharmaceutical Developmental Service. Blood was drawn at 10-rain in':rvals between 10 and 60 min and again at 90 min after m-CPP infusion, and plasma m-CPP levels were measured by high performance liquid chromatography (HPLC-EC) (Murphy et al 1989). Levels were available for SAD patients and controls from the winter study only.
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J.R. J o s e p h - V a n d e r p o o l e t al
SD scores were 17.3 _ 3.7 and atypical depression scores were 14 ± 4.9 (p < 0.05).
Statistical Analysis Baseline behavioral and drug-effect comparisons were made across groups (patients versus controls) and seasons (summer versus winter) by means of two-way analysis of variance (ANOVA). Significant interactive effects were further characterized with Bonferroni-corrected posthoc t-tests. Effects of m-CPP on behavior ratings were assessed by means of ANOVA with repeated measures, with two grouping factors (group and season) and one repeated measure (time). Where the data did not meet the assumption of sphericity, Greenhouse-Geisser corrections (Greenhouse and Geisser 1952) were used. As pali of the repeated measures analysis, each postdrug time was contrasted to baseline to help characterize the time course of drug-induced changes. To remove the possible influence of baselinc differences, we also performed similar ANOVAs on change scores. In addition, significant interactive effects were further characterized by a two-way analysis of variance at each time point accompanied by Bonferroni-corrected posthoc t-tests. Levels of m-CPP were analyzed by the same statistical procedure. Missing values were < 5 % and were interpolated by method of maximum likelihood (BMDP #5V). Unless stated otherwise, all data are presented as means ± SEM. Methods of calculation were those of Statistical Analysis System (SAS Institute, Cary, NC).
Baseline NIMH Self-Rating Scale At baseline, that is before any drug was administered, the groups differed across seasons with respect to several behavioral variables (see Table 1), namely: "activation/euphoria," "depressed affect," "dysphoria,'" and "functional deficit." Posthoc t-tests revealed significantly greater levels of "depressed affect," "dysphoria," "functional deficit," "altered self awareness," and "anxiety" in the winter than in the summer in SAD patients. Patients and controls differed on these behavioral measures during the winter, but not during the summer. In those two N1MH self-rating subsca!es in which there were no significant group-by-season interactions, namely, "altered self awareness" and "anxiety," there were nonetheless main effects: a significant effect of both group and season in the case of "altered self-awareness" (p < 0.05); (p < 0.01) and of season in the case of "anxiety" (p < 0.01). Thus, patients and normals both showed increased "altered self-awareness" (F = 13.49; df = 1,34; p < 0.001) and increased "anxiety" (F = 7.27; df = 1,34; p < 0.01) in winter versus summer. Patients also showed significantly more "altered self-awareness" than controls without regard to seasons (F = 5.2!; df = !,34; p < 0.05).
Results
Baseline Hamilton Depression Ratings
NIMH Self-Rating Scale Following Intravenous m-CPP
SAD patients in the summer had mean ( ___ SEM) baseline (pre m-CPP) Hamilton depression rating scores of 3.25 ± 3.91 and atypical depression scores of 1 ___ 1.06. There was a statistically significant difference between these summer values and those baseline values obtained in our earlier winter studies in which the corresponding mean ±
Given the marked baseline differences on several factors, only the results of the ANOVAs on the change scores will be presented. Patients and normals reacted differently to m-CPP infusions across seasons (i.e., significant groupby-season interaction) only on the "activation/euphoria"
Table 1. Baseline Behavioral Scores from NIMH Self-Rating Factors in SAD Patients and Healthy Controls S A D patients
Activation Altered self-
Controls
Winter
Summer
Winter
Summer
(n = 10)
(n = 9)
(n = 10)
(n = 9)
Type
Season
Type x season
1.0 ± 0.41 ° 3.17 ± 0.58
3.44 "4- 1.33 0.63 - 0.62
3.64 ___ 0.97 ! . 3 6 --- 0.59
1.39 --- 0.73 0.00 ___ 0.00
NS F = 5.21 b
NS F = 13.49 b
F = 6.78 b NS
1.88 0.00 0.00 5.42
6.59 i.36 2.42 3.94
0.56 0.00 0.00 0.37
NS F = 11.36 b F = 4 . 5 9 t' F = 14.24 b
F F F F
NS F = 11.36 b F = 4.5cY' F = 4.62 ~
awa.l~ness
Anxiety Depressed affect Dyspho~a Functional deficit
8.75 13.50 8.00 22.33
-L-_ 2.30 _ 3.14 ± 1.42 _-L-4.84
~AII values expressed as means _ SEM. bp < 0.05; cp < 0.0l Degrees of freedom for all ANOVAs = 1, 34.
~ 1.23 + 0.00 -4- 0.00 _-L- 2.67
-¢_+ -
3.38 1.14 1.80 2.24
_ +_ _+ _
0.37 0.00 0.00 0.37
= = = =
7.27 b 17.04 b 16.03 t' 10.88 b
Behavioral Responsesto m-CPPP in SAD
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Figure 1. Mean "activation/euphoria" ratings following IV administration of m-CPP ia SAD patients and controls in the summer (n = 8 of each group) and winter (n = 9 of each group). Values are adjusted to take into account baseline differences. There is a significant group-by-season interaction (F = 10.15; df = 1,34; p < 0.01) with a greater effect seen ia SAD patients in winter than in normal controls or SAD patients in summer (# differs from winter control at p < 0.05; ** differs from all other groups at p < 0.001).
subscale (F = 10.15; df = 1,34; p < 0.01) (See Figure 1). In other words, far more activation occurred in patients during the winter than in the ~ther three comparison situations (patients in summer; and controls in summer and winter). Significant group-by-time effects were seen after m-CPP only in "altered self-awareness" (F = 6.75; df = 2,68; p < 0.01) ~ d dysphoria ( F = 8.68; df = 2,68; p < 0.01) (See Figures 2a and 2b). A similar pattern of response was seen for the "'depression" factor (See Figure 2c), although this failed to reach statistical significance.
reporting minimum increases, and both patients and controis reporting intermediate effects during the summer.
Drug-Effect Items
Discussion
The only baseline differences between patients and norreals across seasons on the 1 l-item drug-effects form were on "memory.," (F = 12.83; df = 1,34;p < 0.01), "slowed down," (F = 24.02; df = 1,34;p < 0.001), and drowsy (F = 8.29; df = 1,34;p < 0.01), in which SAD patients were more handicapped than normals in winter. When post m-CPP responses were examined and allowances were made for baseline differences, two significant main effects emerged: a significant effect of season on "sleepy" (F = 4.18; df = 1,34;p < 0.05), with both patients and normals reporting more feelings of sleepiness in winter than in summer; and a significant effect of group on "slowed" (F = 13.45; df = 1,34; p < 0.001), with patients reporting feeling less slowed down in relation tc their higher baseline levels than normals, who have lower baseline levels on this item. In addition, there was a significant group-by-season effect on the "dizzy" item (F = 4.93; df = 1,34; p < 0.05), with SAD patients in winter reporting maximum increases in dizziness, normal controls in winter
As one might have predicted, SAD patients and normals differed during the winter on several self-rated measures of psychological functioning, including having more "depression" and "functional deficit" and lower "activation/euphoria" ratings. These differences were not apparent during the summer. These predictable differences between SAD patients and norrnals, confined to certain seasons, validates the construct of SAD as a condition characterized by depression in the winter but not in the summer. Following m-CPP infusions, patients and normals responded differently without regard to season on the subscales, "altered self-awareness" and "dysphoria," which suggests that although they are euthymic during the summer, SAD patients retain a vulnerability to respond to infused m-CPP in an abnormal fashion. Such exaggerated responses in euthymic subjects may represent a trait marker of the diathesis to winter depressions in patients with SAD. The only other putative trait markers of SAD reported to date are low plasma prolactin levels, which have been
m-CPP Levels ANOVA with repeated measures showed no significant group or time effect. Overall mean plateau-phase levels for patients and controls were 25.8 -+ 2.29 and 27.7 _ 3.98, respectively.
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Figure 2(a--c). Mean values for "altered self-awareness," "'dysphoria,'" and "depression" following m-CPP infusions, adjusted to take into account baseline differences. Significant groupby-time effects were seen in "'altered selfawareness" (F = 6.75; df = 2,68; p < O.OI) and dysphoria (F = 8.68; df = 2,68; p < 0.01). A similar pattern of response was seen for "depression," although this failed to reach statistical significance (#p < 0.05, # # p < 0.001; significant difference between both SAD and control groups at that time).
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attributed to abnormal brain dopamine systems (Depue et al 1990), and exaggerated plasma cortisol and prolactin responses to m-CPP infusions (Jacobsen et al 1989). In contrast to these apparent trait markers, the marked increase in activation/euphoria seen after m-CPP infusions in SAD patients in winter was neither evident in patients in the summer nor in normal controls in summer or winter. We have replicated this finding of increased activation/ euphoria in a more recent study of depressed SAD patients in winter (Garcia-Borregeuro D, Schwartz PJ, Murphy DL, Oren DA, Snelbaker AJ, Moul DE, Ozaki N, Falouji WM, Rosenthal NE, unpublished observations, 1992). This exaggerated response was normalized by effective light
therapy, providing further evidence that it is a state marker (Jacobsen et al 1989). We cannot explain why, of all the behavioral responses to m-CPP, increased activation/ euphoria should have emerged as the only state marker. Other state markers of SAD reported previously include: prolonged sleep length and reduced delta sleep (Rosenthal et al 1984; Skwerer et al 1988); abnormally delayed circadian rhythms (Lewy et al 1987; Terman et al 1988; Sack et al 1990); increased peripheral blood lymphocyte responses to mitogen stimulation (Skwerer et al 1988); increased resting metabolic rate (Gaist et al 1990); supersensitivity of melatonin suppression by environmental light (Thompson et al 1990); electrooculogram abnormalities
Behavioral Responses to m-CPPP in SAD
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(Lam et al 1991); and physiological responses attributed to abnormal brain dopaminergic systems, notably increased blink rates and abnormally slow re-equilibration of body temperature following an exercise challenge (Depue et al 1988). Three limitations of this study should be noted. First, different subject groups were studied during the two seasons. A within-subjects design would have provided the advantage of decreased variance between groups. Insofar as a within-subjects design decreases variance, it reduces noise and increased the likelihood that true differences across conditions will be detected. Second, we included no placebo-control condition in this study. Differences between patients and controls could thus be attributed to nonspecific responses to the infusion of any substance. We did, however, build controls into the design in the form of different groups (patients versus normals) and seasons (summer versus winter). Furthermore, our more recent experience with the behavioral effects of m-CPP in SAD patients suggests that they do not have different responses to placebo infusions from controls (Garcia-Borregeuro D, Schwartz P, Murphy DL, Oren DA, Moul D, Ozaki N, Snelbaker A, Rosenthal NE~ unpublished data, 1992). Third, we obtained no m-CPP levels for subjects in the summer study. There were, however, no differences in m-CPP levels between patients and controls during the winter. Thus, different behavioral responses between these two groups in winter cannot be explained in terms of different drug levels. In addition, we have no reason to believe that there would be any between-group differences in blood levels during the summer. The induction of both "depression" and "activation/ euphoria" by m-CPP in SAD patients might have been a function of mixed mood states or, alternatively, of moment-to-moment fluctuations between feelings of "depression" and of "activation/euphoria." Because we asked patients to rate their emotional responses every 30 rain, it is quite possible that high levels of these different emotions were present in the same 30-min epoch, though at different times. Both patients and controls showed a seasonal variation at baseline on the items, "anxiety" and "altered self-awareness." Such seasonal variations in affect in normal subjects is compatible with the findings of epidemiological studies conducted in the same geographical area as the present clinical study. Thus, Kasper and coworkers (1989) and Rosen and coworkers (1989) found that 43% and 48% of two normal samples, respectively, reported feeling worse during the winter months. There is extensive evidence of seasonal variations in biological measures, including some pertaining to serotonergic systems in normal human subjects (Lacoste and Wirz-Justice 1989). Patients and normals responded similarly on the t,hysical symptom items on the "drug-effects" questionnair :.
Insofar as the "drug-effects" questionnaire is mainly designed to measure the physical effects of the drug, the similarity in responses to questions about physical e,~fects would suggest that the differential responses seen in SAD patients on the NIMH questionnaire are more likely to be caused by direct effects on the brain, than by responses to physical effects of the m-CPP infusion. In fact, the differences between patients and normal controls following m-CPP infusion were seen on only two items, "'slowed" and "dizzy," both presumably mediated by effects, of the drug on the brain. The decreased feelings of be,rig slowed down reported by SAD patients following m-CPP infusion were consistent with their increased activation/euphoria, as measured by the NIMH Self-rating scale. What might these atypical responses of SAD patients to m-CPP signify? Insofar as m-CPP is a serotonergic agonist, they might reflect an abnormality in the functioning of a brain serotonin subsystem, m-CPP stimulates several serotonin receptors and binds to other types of receptors such as alpha2-adrenergic receptors (Murphy et al 1991; Kahn and Wetzler 1991). Binding site and behavioral studies in rats suggest that 5-HT~c receptors may be the most likely candidates for the observed m-CPP effects (Berendsen et al 1990; Fozard and Gray 1989; Kennett and Curzon 1988a; Kennett and Curzon 1988b; Kennett et al 1989; Murphy et al 1991), although other receptors should also be considered. There are other reasons to suspect serotonergic involvement in SAD, a possibility we raised in our original description of the syndrome (Rosenthal et al 1984). The abnormally activating effects of carbohydrate-rich meals on SAD patients during the winter (Rosenthal et al 1989) might reflect abnormal brain serotonergic responsivity, given the evidence, at least in animals, that carbohydrate-rich meals promote the entry of tryptophan into the brain and the synthesis of serotonin (Fernstrom an~ Wurtman 1971; •,lr..~v, ut tu,au a~lua ,X~,..-,m~,, u, ,.,,~, J., u../.~Q~O~ ~.'=~,,~,,,~h~,,.,:V,~r,,,~.given r,r~lly~.... has been reported to be helpful in some SAD patients (McGrath et al 1990). More recently, the serotonin releasing agent, d-fenfluramine, has been shown to be effective in the treatment of SAD (O'Rourke et al 1989). A postmortem study performed on the brains of individuals who had died of nonpsychiatric, nonneurological disorders, revealed a sharp drop in hypothalamic serotonin concentration during the winter (Carlsson et al 1980). Several other measures of serotonin metabolism in humans have also been shown to vary seasonally (Lacoste and WirzJustice 1989). We hypothesize that a natural tendency for hypothalamic serotonin concentration to decrease during the winter months, perhaps as a result of naturally decreasing environmental light, may lead to the symptoms of SAD in vulnerable individuals, as well as to supersensitivity .of postsynaptic serotonin receptgrs, including 5HT~c recep.
.
.
.
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BIOL PSYCHIATRY 1993;33:496--504
tors. Such supersensitivity would explain the exaggerated behavioral response to the scrotonin agonist, m-CPP, observed in this study. Interventions that increase serotonin availability at the synapse, such as d-fenfluramine or fluoxetine, would be expected to improve the symptoms of SAD, which conforms with anecdotal and scientific observations. According to this hypothesis, light might exert its antidepressant effects by increasing the availability of serotonin at the synapse, which would be expected to downregulate postsynaptic serotonin receptors. Indeed, we have found some normalization of the aberrant behavioral responses of SAD patients to m-CPP in winter following light therapy (Jacobsen et al 1989). In support of this hypothesis, neurophysiological studies in rats have shown that light stimulates the firing of serotonergic neurones (Mason 1986) and there is evidence of a retinal projection to the midbrain raphe in the cat (Foote et al 1978). Oepue and colleagues (1990) have suggested that dopaminergic disturbances may be of central importance in the pathogenesis of SAD and that the antidepressant effects of light may be mediated by its effects on dopaminergic systems. Recent studies by our group have thrown into question the importance of aberrant brain dopaminergic systems in SAD as we were not able to replicate the abnormal eyeblink rate reported by Depue et al (Barbato G, Moul DE, Schwartz PJ, Rosenthal NE, Oren DA, in press) ,rod foand the dopamine precursor, levodopa, to be no better than placebo in the treatment of SAD (Oren DA, Moul DE, Schwartz PJ, Wehr TA, Rosenthal NE, unpublished data, 1992). Insofar as there are many interactions between the serotonergic and dopaminergic systems (Cools 1974; Blandina et al 1988L it may not be necessary, however, to choose between these neurotransmitters in attempting to find the pathophysiological basis for SAD. Indeed, they might be disordered in concert with each other, and light therapy may influence both systems. S.nadies of the behavioral effects of m-CPP adminis~ation have previously been undertaken in patients with other conditions (Murphy et al 1991; Kahn and We~ler 199!), for example, panic disorder (Charney et al 1988; Kahn et
J.R. Joseph-Vanderpool et al
al 1988) obsessive compulsive disorder (Chamey et al 1988; Zohar et al 1987), schizophrenia (Seibyl et al 1991) and Alzheimer's d|sease (Lawlor et al 1989). Results have been variable, with some studies showing no difference between patients and normals. Other studies, however, have shown exacerbation of symptoms. Thus, panic-disorder patients developed panic attacks to a greater degree than controls (Kahn et al 1988); obsessive-compulsive disorder patients developed an exacerbation of obsessivecompulsive symptoms (Zohar et al 1987); schizophrenics became more psychotic (Seibyl et al 1991); and Alzheimer's disease patients became more forgetful (Lawlor et al 1989). Other, nonspecific effects were also noted following m-CPP administration in the above studies. Little work has been done e ~. the effects of m-CPP in nonseasonally depressed patients. In an acute study of oral mCPP administration, depressed patients did qot differ from controls with respect to effects on mood (Kahn et al 1990), whereas in a preliminary study using 2-week periods of drug administration, m-CPP appeared to lead to reduced levels of depression and anxiety in some patients (Mellow et al 1990). The very large increase in "'activation/euphoria'" reported by SAD patients in the winter appears to be somewhat specific to this group. Although healthy volunteers have reported increased self-ratings of "activation/euphoria" after m-CPP, these changes were considerably smaller and represented statistically significant changes only in large subject groups (Mueiler et al 1985; Murphy et al 1989). Seasonal variation in response to m-CPP has not previously been documented, but given the well-documented variation in serotonin metabolism in humans, one might expect to find seasonal variations in other groups. Thus, season of study should be regarded as a potential source of variance in this challenge paradigm, as in other tests of serotonergic function. Insofar as the responses of SAD patients and noL:m.a!controls to m-CPP infusions differed across seasons, the results of this study provide further evidence of dysregulation of serotonergic systems in SAD.
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Barbato G, Moul DE, Schwartz PJ, Rosenthal NE, Oren DA. Spontaneous eye blink rate in winter seasonal affective disorder. Psychiatry Res, in press.
Charney DS, Goodman WK, Price LH, Woods SW, Rasmussen SA, Heninger GR (1988): Serotonin functions in obsessivecompulsive disorder: A comparison of the effects of tryptophan and m-chlorophenylpiperazine in patients and healthy subjects. Arch Gen Psychiatry 45:177-185.
Berendsen HHG, Jenck F, Broekkamp CLE (1990): Involvement of 5-HT 1C-receptors in drug-induced penile erections on rats Psychopharmacology 101:57-61. Blandina P, Goldfarb J, Green J (1988): Activation of 5-HT3 -=-ceptorreleases dopamine from rat striatal slice. Eur J Pharmacol 155:349-350.
Cools A (1974): The transsynaptie relationship between dopamine serotonin in the caudate nucleus of cats. Psychopharmacology 36:17-28. Curzon G (1990): Serotonin and appetite. In Whitaker-Azmitia
Behavioral Responses to m-CPPP in SAD
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Kahn RS, Wemer S (1991): m-C~lorophenylpiperazine as a probe of serotonin function. Bid Psychiatry 30:1139-1166. Kahn R, Wetzler S, Asnis G, Papolos D, Van Praag H (1990): Serotonin receptor sensitivity in major depression. Biol Psychiatry 28:358-362. Kaspcr S, Wehr TA, Bariko JJ, Gaist PA, Rosenthal NE ( 1989): Epidemiological findings of seasonal changes in mood and behavior. Arch Gen Psychiatry 46:823-833. Kennett GA, Curzon G (1988a): Evidence that m-CPP may have behavioural effects mediated by central 5-HTIC receptors. Br J Pharmacoi 94:137-147. Kennett GA, Curzon G (1988b): Evidence that the hypophagia induced by m-CPP and TFIvIPP requires 5-HTIC and 5-HTI B receptors; hypophagia induced by RU24969 only requires 5HTIB receptors. Psychopharmacology 96:93-100. Kennettt GA, Whitton P, Shah K, Carzon G (1989): Anxiogeniclike effects of mCPP and TFMPP in animals models are opposed by 5-HTIC receptor antagonists. Fur J Pharmacol 164:445-454. Lacoste V, WirzJustice A (1989): Seasonal variation in normal subjects: An update of variables current in depression research. In Rosenthal NE, Blehar MC (eds), Seasonal Affective Disorders and Phototheropy. New York: Guilford Press. Lam RW, Beattie CW, Buchanan A, Remick RA, Zis AP (1991): Low electrooculographic ratios in patients with seasonal affective disorder. Am J Psychiatry 148:1526-1529. Lawlor B, Sunderland T, Mellow A, Hill J, Molchan S, Murphy D (1989): Hyperresponsivity to the serotonin agonist m-Chlorophenylpiperazine in Alzheimer's disease. Arch Gen Psychiatry 46:542-549. Lewy AJ, Sack RL, Miller LS, Hobart TM (1987): Antidepressant and circadian phase=shifting effects of light. Science 235:352-353. Mason R (1986): Circadian variation in sensitivity of suprachiasmatic and lateral geniculate ne~.rones to 5-hydroxytryptamine in the rat. d Physiol 377:1-13. McGrath RE, Buckwald B, Resnick EV (1990): The effect of L-tryptophan on seasonal affective disorder. J Clin Psychiciry 51(4):162-163. Mellow AM, Lawlor BA, Sunderland T, Mueller EA, Molchan c~ ~A,,,.~t~,,Dl t =ooa~. Eff~ts of d~!y oral m-chlorophenylpiperazine in elderly depressed patients: initial experience with a seratonin agonist. Biol Psychiatry 28:588-594. Meltzer HY (1990): Role of serotonin in depression. In WhitakerAzmitia PM, Peroutka S] (eds), The Neuropharmacology of Serotonin. New York: The New York Academy of Sciences, pp 486--5OO Molineaux S, Jessel! T, Axel R, Julius D ( 1989): 5-HTlc receptor is a prominent receptor subtype in the central nervous system. Proc Natl Acad Sci USA 86:6793-6797. Mueller EA, Murphy DL, Sunderland T (1985): Neuroeococrine effects of m-chlorophenylpiperazine, a serotonin agonist in humans. J Clin Endocrinol Metab 61(6): 1179-1184. Murphy DL, Mueller EA, Hill JL, Tolliver TJ, Jacobsen FM (1989): Comparative axiogenic, nearoendocrine, and other physiologic effects of m-chlorophenylpiperazine given intravenously or orally to healthy volunteers. Psychopharmacology 98:275-282.
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Murphy DL, Lesch KP, Auklakh Cb, , ~,~.:t I'A [ 19~)1): Serotonin-selective arylpiperazines with neuroenaocrine, behavioral, temperature, and cardiovascular effects in humans. Pharmacol Rev 43(4):527-552. O'Rourke D, Wurtman JJ, Wurtrnan RJ, Chebli R, Gleason R (1989): Treatment of seasonal depression with d-fenfluramine. J Clin Psychiatry 50:343-347. Rosen LM, Targum SD, Terman M, et al (1989): Prevalence of seasonal affective disorder at four latitudes. Psychiatry Res 31:131-144. Rosenthal N, Heffeman M (1986): Bulimia, carbohydrate craving, and depression: a central connection? In Wurtman RJ, Wurtrnau JJ (eds), Nutrition and the Bra;n, New York: Raven Press, pp 139-166. Rosenthal NE, Sack DA, Gillin JC, et al (1984): Seasonal affective disorder: A description of the syndrome and preliminary findings with light therapy. Arch Gen Psychiatr 3, 41:7280. Rosenthal N, Genhart M, Caballero B, et al (1989): Psychobiological effects of carbohydrate- and protein-rich meals in patients with seasonal affective disorder and normal controls. Biol Psychiatry 25:1029-1040. Sack RL, Lewy AJ, White DM, Singer CM, Fireman MJ, Vandiver R (1990): Morning versus evening light treatment for winter depression: Evidence that the therapeutic effects of light are mediated by circadian phase shifts. Arch Gen Psychiatr3., 47:343-351. Seibyl JP, Krystal JH, Price LH, et al (1989): Neuroendocrine
J.R. Joseph-Vanderpool et al
and behavioral responses to m-CPP in unmedicated schizophrenics and heaithy subjects. Proc ACNP, p 122. Skwerer RG, Jacobsen FM, Duncan CC, et al (1988): Neurobiology of seasonal affective disorder and phototherapy. J Biol Rhythms 3:135-154. Spitzer R, Williams J, Gibbon M (1986): Structured Clinical Interview for DSM-III-R. New York: Biometrics Research Department, New York State Psychiatric Institute, Terman M (1989): On the question of mechanism in phototherapy for seasonal affective disorder: Considerations, clinical efficacy and epidemiology. In Rosenthal N, Blehar M (eds), Seasonal Affective Disorders and Phototherap.v. New York: Guilford Press. Terman M, Terman JS, Quitkin FM, et al (1988): Response of the melatonin cycle to phototherapy for seasonal affective disorder, J Neural Transm 72:147-165. Thompson C, Stinson D, Smith A (1990): Seasonal affective disorder and season dependent abnormalities of melatonin suppression by light. Lancet 336:703-706. van Kammen DP, Murphy DL (1975): Attenuation of the euphoriant and activation effects of d- and t-amphetamine by lithium carbonate treatment. Psychopharmacologia 44:215244. Wurtman RJ, Wurtman JJ (1989): Carbohydrates and depression. Sci Am 260:68-75. Zohar J, Insel T, Zohar-Kadouch R, Hill J, Murphy D (1987): Serotonergic responsivity in obsessive-compulsive disorder. Effects of chronic clomipramine treatment. Arch Gen Psychiatry 44:946.
BIOL PSYCHIATRY 1993;33:496--504
Seasonal Variation in Behavioral Responses to m-CPP in Patients with Seasonal Affective Disorder and Controls Jean R. Joseph-Vanderpool, Frederick M. Jacobsen, Dennis L. Murphy, James L. Hill, and Norman E. Rosenthal
Thts paper reports the behavioral responses to m-chlorophenylpib~erazine (m-CPP), a serotonin agonist, in patients with seasonal affective disorder (SAD) and controls during the summer. Results are compared with the responses of SAD patients and controls given m-CPP in the winter. Results of the winter study were reported earlier by our group. Baseline Hamilton depression ratings in SAD patients were significantly lower in the summer than in winter (p < 0.05). Additionally, in both SAD patients and controls, there were seasonal differences on the National Institute of Mental Health (NIMH ) self-rating scale items: "depressed affect," "dysphoria," and "functional deficit" at baseline. The behavioral responses to m-CPP across seasons differentiated patients from normals only in the "activation~euphoria'" item, on which afar greater response was seen in patients than in controls during the winter. This behavioral response may be a state marker for winter depression, as it was significantly reduced after light treatment of these patients in the winter, and in the summer, SAD patients responded differently from4controls on "altered self-awareness" and "dysphoria " independently of seasons, and these responses may be considered as possible trait markers for this condition. These results provide further evidence of a possible deficiency in serotonergic trattemis~ion in seasonal affective disorder.
Key Words: Seasonal affective disorder, seasons, light, serotonin, depression, circadian rhythms
Introduction Winter seasonal aff,.ctive disorder (SAD) is characterized by recurrent winter depressions alternating with nonde-
the Section on Environmental Psychiatry. Clinical Psychobiology Branch, NIMH, Bethesda,/riD. Address reprmt requests to Norman E. Roseothal, MD, Chief, Section on Environmental Psychiatry, Clinical Psychobiology Branch, NIMH, Bid. 10 Rm 4S/239, 9000 Rockville Pike, Bethesda, MD 20892. Received March 31. 1992; revised November20, 1992. From
© 1993 Society of Biological Psychiatry
pressed periods in spring and summer (Rosenthal c~ al 1984). During the winter, SAD patients often gain weight, crave carbohydrates, oversleep, and are lethargic. In contrast, they often lose weight, sleep less, and are more energetic in the summer when their depressions remit. Because several of the above behaviors are thought to be modulated by brain serotonin systems (Meltzer 1990; Curzon 1990; Jimerson et al 1990), a dysregulation of serotonergic transmission has been postulated in SAD (Rosenthal et al i984; Jacobsen et al 1989). 0006-3223/93/$06.00
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Speculation about serotonergic disturbances in SAD stems from several pieces of information: First, there is extensive evidence of seasonal variations in serotonergic systems in humans (Lacoste and Wirz-Justice 1989). Second, d-fenfluramine, a serotonin agonist, has been found to be effective in treating SAD patients (O'Rourke et al 1989). Third, SAD patients report feeling more activated following a high-carbohydrate meal compared to controls, who report feeling more sedated (Rosenthal et ai 1989). Because dietary carbohydrate intake is thought to affect brain serotonin synthesis and transmission (Fernstrom and Wurtman 1971; Wurtman and Wurtman 1989), this aberrant response may reflect serotonergic dysregulation. In addition, carbohydrate craving and increased carbohydrate intake, which are characteristic winter symptoms in SAD patients, may reflect a behavioral attempt to normalize this putative serotonergic abnormality (Rosenthal et al 1984). Finally, depressed SAD patients have reported increased activation and euphoria following intravenous infusions of the serotonergic agonist, m-CPP, during the winter, and these behavioral responses to m-CPP ~.~fusions we.re ~ttenanted and no.-malized after light therapy Oacebsen et al 1989). In order to determine whether the atypical behavioral responses of SAD patients to m-CPP are a reflection of their winter depressed state or a possible trait marker for SAD, we repeated the m-CPP infusion paradigm in a new group of euthymic SAD patients and a group of normal controls during the summer. We report here on the findings of this study and compare the new results with the findings of our earlier winter study.
Materials and Methods Subjects
Subjects who participated in the summer study were eight SAD patients, (four women and four men) and nine controis (five women and four men). Mean age ( ± SD) of SAD patients was 39.3 -+ 9. !, and of the controls was 37 _+ 8.7. All subjects were outpatient ; during the course of the study, and all gave informed voluntary written consent for their participation. The groups were chosen so that they resembled in demographic profile those studied previously by our group in the winter. Thus, in the earlier winter study there were l0 patients (7 women and 3 men) and l I controls (8 women and 3 men), whose mean ages ( ± SD) were 40 ± 7.9 and 41 ± 9.3 years, respectively. For the control group we selected women of similar menstrual status to those in the patient group. All patients met diagnostic criteria of Rosenthal et al (1984) tor seasonal affective disorder and i'ur major depression with seasonal pattern, as defined by the Diagnostic and Statistical Manual for Psychiatric Disorder (DSM-III-
R) (American Psychiatric Association 1987). None of the controls had any history of psychiatric disorders, as determined by Structured Clinical Interview for DSM-III-R (SCID) (Spitzer et al 1986). All subjects underwent routine physical examinations and laboratory tests before the study. Botch patients and controls were medically healthy and medication free for at least 4 weeks before the study. Patients were rated by trained blind raters, who administered the 21-item Hamilton Depressive Rating Scale (HDRS) (Hamilton 1967) along with seven atypical depressive items that have been shown to have particular relevance to SAD (Rosenthal and Heffernan 1986). Procedures
Following an overnight fast, indwelling venous catheters were inserted into forearm veins of both arms at 8:30 Arvl and kept patent with hepadnized normal saline solution. Subjects were instructed to sit in reclining chairs and were permitted to read, knit, watch television, or perform desk work dufiq~ the course of the study. After insertion of the IV, subjects were adapted to the experimental conditions until 9:50 AM. They were then asked to complete a series of rating forms including the NIMH 24-item self-rating scale (Van Kammen and Murphy 1975; Murphy et al 1989) as well as the appended items, ("have suicidal thoughts," "have repetitive thoughts," and "feel like eating sweets/starches"), the Stanford Sleepiness Scale (Hoddes et al 1973), and 10 drug-effect items. Drug-effect items were rated on a fourpoint scale (none, slight, moderate, much) and included the items "slowed down," "drowsy/sleepy," "chilled," "lightheaded/dizzy," "trouble remembering/concentrating," "yawning," "hot/flushed feeling," "visual changes," "nauseated," and "headache." The two other items, "vomiting" and "penile erection" were rated either "Yes" or "No." Six subscale scores were compiled from the NIMH 24-item scale as previously described: "activation/euphoria," "depressed atlect,-~ . . . . . . . zmxie a,t~,.u o,,,-a . . . . . . . . . "functional deficit," and "dysphoria" (Van Kammen and Murphy 1975; Murphy et al 1989). Subjects were given m-CPP, 0.1 mg/kg IV over 90 sec at 10 AM (0 min) after the first battery of ratings scales had been completed. Administration of rating sca!es was repeated at 30, 60, and 90 min after m-CPP was infused. The investigators obtained m-CPP from Aldrich Pharmaceutical Co (Milwaukee, WI) and it was prepared by the National Institutes of Health (NIH) Pharmaceutical Developmental Service. Blood was drawn at 10-rain in':rvals between 10 and 60 min and again at 90 min after m-CPP infusion, and plasma m-CPP levels were measured by high performance liquid chromatography (HPLC-EC) (Murphy et al 1989). Levels were available for SAD patients and controls from the winter study only.
498
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J.R. J o s e p h - V a n d e r p o o l e t al
SD scores were 17.3 _ 3.7 and atypical depression scores were 14 ± 4.9 (p < 0.05).
Statistical Analysis Baseline behavioral and drug-effect comparisons were made across groups (patients versus controls) and seasons (summer versus winter) by means of two-way analysis of variance (ANOVA). Significant interactive effects were further characterized with Bonferroni-corrected posthoc t-tests. Effects of m-CPP on behavior ratings were assessed by means of ANOVA with repeated measures, with two grouping factors (group and season) and one repeated measure (time). Where the data did not meet the assumption of sphericity, Greenhouse-Geisser corrections (Greenhouse and Geisser 1952) were used. As pali of the repeated measures analysis, each postdrug time was contrasted to baseline to help characterize the time course of drug-induced changes. To remove the possible influence of baselinc differences, we also performed similar ANOVAs on change scores. In addition, significant interactive effects were further characterized by a two-way analysis of variance at each time point accompanied by Bonferroni-corrected posthoc t-tests. Levels of m-CPP were analyzed by the same statistical procedure. Missing values were < 5 % and were interpolated by method of maximum likelihood (BMDP #5V). Unless stated otherwise, all data are presented as means ± SEM. Methods of calculation were those of Statistical Analysis System (SAS Institute, Cary, NC).
Baseline NIMH Self-Rating Scale At baseline, that is before any drug was administered, the groups differed across seasons with respect to several behavioral variables (see Table 1), namely: "activation/euphoria," "depressed affect," "dysphoria,'" and "functional deficit." Posthoc t-tests revealed significantly greater levels of "depressed affect," "dysphoria," "functional deficit," "altered self awareness," and "anxiety" in the winter than in the summer in SAD patients. Patients and controls differed on these behavioral measures during the winter, but not during the summer. In those two N1MH self-rating subsca!es in which there were no significant group-by-season interactions, namely, "altered self awareness" and "anxiety," there were nonetheless main effects: a significant effect of both group and season in the case of "altered self-awareness" (p < 0.05); (p < 0.01) and of season in the case of "anxiety" (p < 0.01). Thus, patients and normals both showed increased "altered self-awareness" (F = 13.49; df = 1,34; p < 0.001) and increased "anxiety" (F = 7.27; df = 1,34; p < 0.01) in winter versus summer. Patients also showed significantly more "altered self-awareness" than controls without regard to seasons (F = 5.2!; df = !,34; p < 0.05).
Results
Baseline Hamilton Depression Ratings
NIMH Self-Rating Scale Following Intravenous m-CPP
SAD patients in the summer had mean ( ___ SEM) baseline (pre m-CPP) Hamilton depression rating scores of 3.25 ± 3.91 and atypical depression scores of 1 ___ 1.06. There was a statistically significant difference between these summer values and those baseline values obtained in our earlier winter studies in which the corresponding mean ±
Given the marked baseline differences on several factors, only the results of the ANOVAs on the change scores will be presented. Patients and normals reacted differently to m-CPP infusions across seasons (i.e., significant groupby-season interaction) only on the "activation/euphoria"
Table 1. Baseline Behavioral Scores from NIMH Self-Rating Factors in SAD Patients and Healthy Controls S A D patients
Activation Altered self-
Controls
Winter
Summer
Winter
Summer
(n = 10)
(n = 9)
(n = 10)
(n = 9)
Type
Season
Type x season
1.0 ± 0.41 ° 3.17 ± 0.58
3.44 "4- 1.33 0.63 - 0.62
3.64 ___ 0.97 ! . 3 6 --- 0.59
1.39 --- 0.73 0.00 ___ 0.00
NS F = 5.21 b
NS F = 13.49 b
F = 6.78 b NS
1.88 0.00 0.00 5.42
6.59 i.36 2.42 3.94
0.56 0.00 0.00 0.37
NS F = 11.36 b F = 4 . 5 9 t' F = 14.24 b
F F F F
NS F = 11.36 b F = 4.5cY' F = 4.62 ~
awa.l~ness
Anxiety Depressed affect Dyspho~a Functional deficit
8.75 13.50 8.00 22.33
-L-_ 2.30 _ 3.14 ± 1.42 _-L-4.84
~AII values expressed as means _ SEM. bp < 0.05; cp < 0.0l Degrees of freedom for all ANOVAs = 1, 34.
~ 1.23 + 0.00 -4- 0.00 _-L- 2.67
-¢_+ -
3.38 1.14 1.80 2.24
_ +_ _+ _
0.37 0.00 0.00 0.37
= = = =
7.27 b 17.04 b 16.03 t' 10.88 b
Behavioral Responsesto m-CPPP in SAD
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Figure 1. Mean "activation/euphoria" ratings following IV administration of m-CPP ia SAD patients and controls in the summer (n = 8 of each group) and winter (n = 9 of each group). Values are adjusted to take into account baseline differences. There is a significant group-by-season interaction (F = 10.15; df = 1,34; p < 0.01) with a greater effect seen ia SAD patients in winter than in normal controls or SAD patients in summer (# differs from winter control at p < 0.05; ** differs from all other groups at p < 0.001).
subscale (F = 10.15; df = 1,34; p < 0.01) (See Figure 1). In other words, far more activation occurred in patients during the winter than in the ~ther three comparison situations (patients in summer; and controls in summer and winter). Significant group-by-time effects were seen after m-CPP only in "altered self-awareness" (F = 6.75; df = 2,68; p < 0.01) ~ d dysphoria ( F = 8.68; df = 2,68; p < 0.01) (See Figures 2a and 2b). A similar pattern of response was seen for the "'depression" factor (See Figure 2c), although this failed to reach statistical significance.
reporting minimum increases, and both patients and controis reporting intermediate effects during the summer.
Drug-Effect Items
Discussion
The only baseline differences between patients and norreals across seasons on the 1 l-item drug-effects form were on "memory.," (F = 12.83; df = 1,34;p < 0.01), "slowed down," (F = 24.02; df = 1,34;p < 0.001), and drowsy (F = 8.29; df = 1,34;p < 0.01), in which SAD patients were more handicapped than normals in winter. When post m-CPP responses were examined and allowances were made for baseline differences, two significant main effects emerged: a significant effect of season on "sleepy" (F = 4.18; df = 1,34;p < 0.05), with both patients and normals reporting more feelings of sleepiness in winter than in summer; and a significant effect of group on "slowed" (F = 13.45; df = 1,34; p < 0.001), with patients reporting feeling less slowed down in relation tc their higher baseline levels than normals, who have lower baseline levels on this item. In addition, there was a significant group-by-season effect on the "dizzy" item (F = 4.93; df = 1,34; p < 0.05), with SAD patients in winter reporting maximum increases in dizziness, normal controls in winter
As one might have predicted, SAD patients and normals differed during the winter on several self-rated measures of psychological functioning, including having more "depression" and "functional deficit" and lower "activation/euphoria" ratings. These differences were not apparent during the summer. These predictable differences between SAD patients and norrnals, confined to certain seasons, validates the construct of SAD as a condition characterized by depression in the winter but not in the summer. Following m-CPP infusions, patients and normals responded differently without regard to season on the subscales, "altered self-awareness" and "dysphoria," which suggests that although they are euthymic during the summer, SAD patients retain a vulnerability to respond to infused m-CPP in an abnormal fashion. Such exaggerated responses in euthymic subjects may represent a trait marker of the diathesis to winter depressions in patients with SAD. The only other putative trait markers of SAD reported to date are low plasma prolactin levels, which have been
m-CPP Levels ANOVA with repeated measures showed no significant group or time effect. Overall mean plateau-phase levels for patients and controls were 25.8 -+ 2.29 and 27.7 _ 3.98, respectively.
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Figure 2(a--c). Mean values for "altered self-awareness," "'dysphoria,'" and "depression" following m-CPP infusions, adjusted to take into account baseline differences. Significant groupby-time effects were seen in "'altered selfawareness" (F = 6.75; df = 2,68; p < O.OI) and dysphoria (F = 8.68; df = 2,68; p < 0.01). A similar pattern of response was seen for "depression," although this failed to reach statistical significance (#p < 0.05, # # p < 0.001; significant difference between both SAD and control groups at that time).
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attributed to abnormal brain dopamine systems (Depue et al 1990), and exaggerated plasma cortisol and prolactin responses to m-CPP infusions (Jacobsen et al 1989). In contrast to these apparent trait markers, the marked increase in activation/euphoria seen after m-CPP infusions in SAD patients in winter was neither evident in patients in the summer nor in normal controls in summer or winter. We have replicated this finding of increased activation/ euphoria in a more recent study of depressed SAD patients in winter (Garcia-Borregeuro D, Schwartz PJ, Murphy DL, Oren DA, Snelbaker AJ, Moul DE, Ozaki N, Falouji WM, Rosenthal NE, unpublished observations, 1992). This exaggerated response was normalized by effective light
therapy, providing further evidence that it is a state marker (Jacobsen et al 1989). We cannot explain why, of all the behavioral responses to m-CPP, increased activation/ euphoria should have emerged as the only state marker. Other state markers of SAD reported previously include: prolonged sleep length and reduced delta sleep (Rosenthal et al 1984; Skwerer et al 1988); abnormally delayed circadian rhythms (Lewy et al 1987; Terman et al 1988; Sack et al 1990); increased peripheral blood lymphocyte responses to mitogen stimulation (Skwerer et al 1988); increased resting metabolic rate (Gaist et al 1990); supersensitivity of melatonin suppression by environmental light (Thompson et al 1990); electrooculogram abnormalities
Behavioral Responses to m-CPPP in SAD
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1993:33:4%--504
(Lam et al 1991); and physiological responses attributed to abnormal brain dopaminergic systems, notably increased blink rates and abnormally slow re-equilibration of body temperature following an exercise challenge (Depue et al 1988). Three limitations of this study should be noted. First, different subject groups were studied during the two seasons. A within-subjects design would have provided the advantage of decreased variance between groups. Insofar as a within-subjects design decreases variance, it reduces noise and increased the likelihood that true differences across conditions will be detected. Second, we included no placebo-control condition in this study. Differences between patients and controls could thus be attributed to nonspecific responses to the infusion of any substance. We did, however, build controls into the design in the form of different groups (patients versus normals) and seasons (summer versus winter). Furthermore, our more recent experience with the behavioral effects of m-CPP in SAD patients suggests that they do not have different responses to placebo infusions from controls (Garcia-Borregeuro D, Schwartz P, Murphy DL, Oren DA, Moul D, Ozaki N, Snelbaker A, Rosenthal NE~ unpublished data, 1992). Third, we obtained no m-CPP levels for subjects in the summer study. There were, however, no differences in m-CPP levels between patients and controls during the winter. Thus, different behavioral responses between these two groups in winter cannot be explained in terms of different drug levels. In addition, we have no reason to believe that there would be any between-group differences in blood levels during the summer. The induction of both "depression" and "activation/ euphoria" by m-CPP in SAD patients might have been a function of mixed mood states or, alternatively, of moment-to-moment fluctuations between feelings of "depression" and of "activation/euphoria." Because we asked patients to rate their emotional responses every 30 rain, it is quite possible that high levels of these different emotions were present in the same 30-min epoch, though at different times. Both patients and controls showed a seasonal variation at baseline on the items, "anxiety" and "altered self-awareness." Such seasonal variations in affect in normal subjects is compatible with the findings of epidemiological studies conducted in the same geographical area as the present clinical study. Thus, Kasper and coworkers (1989) and Rosen and coworkers (1989) found that 43% and 48% of two normal samples, respectively, reported feeling worse during the winter months. There is extensive evidence of seasonal variations in biological measures, including some pertaining to serotonergic systems in normal human subjects (Lacoste and Wirz-Justice 1989). Patients and normals responded similarly on the t,hysical symptom items on the "drug-effects" questionnair :.
Insofar as the "drug-effects" questionnaire is mainly designed to measure the physical effects of the drug, the similarity in responses to questions about physical e,~fects would suggest that the differential responses seen in SAD patients on the NIMH questionnaire are more likely to be caused by direct effects on the brain, than by responses to physical effects of the m-CPP infusion. In fact, the differences between patients and normal controls following m-CPP infusion were seen on only two items, "'slowed" and "dizzy," both presumably mediated by effects, of the drug on the brain. The decreased feelings of be,rig slowed down reported by SAD patients following m-CPP infusion were consistent with their increased activation/euphoria, as measured by the NIMH Self-rating scale. What might these atypical responses of SAD patients to m-CPP signify? Insofar as m-CPP is a serotonergic agonist, they might reflect an abnormality in the functioning of a brain serotonin subsystem, m-CPP stimulates several serotonin receptors and binds to other types of receptors such as alpha2-adrenergic receptors (Murphy et al 1991; Kahn and Wetzler 1991). Binding site and behavioral studies in rats suggest that 5-HT~c receptors may be the most likely candidates for the observed m-CPP effects (Berendsen et al 1990; Fozard and Gray 1989; Kennett and Curzon 1988a; Kennett and Curzon 1988b; Kennett et al 1989; Murphy et al 1991), although other receptors should also be considered. There are other reasons to suspect serotonergic involvement in SAD, a possibility we raised in our original description of the syndrome (Rosenthal et al 1984). The abnormally activating effects of carbohydrate-rich meals on SAD patients during the winter (Rosenthal et al 1989) might reflect abnormal brain serotonergic responsivity, given the evidence, at least in animals, that carbohydrate-rich meals promote the entry of tryptophan into the brain and the synthesis of serotonin (Fernstrom an~ Wurtman 1971; •,lr..~v, ut tu,au a~lua ,X~,..-,m~,, u, ,.,,~, J., u../.~Q~O~ ~.'=~,,~,,,~h~,,.,:V,~r,,,~.given r,r~lly~.... has been reported to be helpful in some SAD patients (McGrath et al 1990). More recently, the serotonin releasing agent, d-fenfluramine, has been shown to be effective in the treatment of SAD (O'Rourke et al 1989). A postmortem study performed on the brains of individuals who had died of nonpsychiatric, nonneurological disorders, revealed a sharp drop in hypothalamic serotonin concentration during the winter (Carlsson et al 1980). Several other measures of serotonin metabolism in humans have also been shown to vary seasonally (Lacoste and WirzJustice 1989). We hypothesize that a natural tendency for hypothalamic serotonin concentration to decrease during the winter months, perhaps as a result of naturally decreasing environmental light, may lead to the symptoms of SAD in vulnerable individuals, as well as to supersensitivity .of postsynaptic serotonin receptgrs, including 5HT~c recep.
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tors. Such supersensitivity would explain the exaggerated behavioral response to the scrotonin agonist, m-CPP, observed in this study. Interventions that increase serotonin availability at the synapse, such as d-fenfluramine or fluoxetine, would be expected to improve the symptoms of SAD, which conforms with anecdotal and scientific observations. According to this hypothesis, light might exert its antidepressant effects by increasing the availability of serotonin at the synapse, which would be expected to downregulate postsynaptic serotonin receptors. Indeed, we have found some normalization of the aberrant behavioral responses of SAD patients to m-CPP in winter following light therapy (Jacobsen et al 1989). In support of this hypothesis, neurophysiological studies in rats have shown that light stimulates the firing of serotonergic neurones (Mason 1986) and there is evidence of a retinal projection to the midbrain raphe in the cat (Foote et al 1978). Oepue and colleagues (1990) have suggested that dopaminergic disturbances may be of central importance in the pathogenesis of SAD and that the antidepressant effects of light may be mediated by its effects on dopaminergic systems. Recent studies by our group have thrown into question the importance of aberrant brain dopaminergic systems in SAD as we were not able to replicate the abnormal eyeblink rate reported by Depue et al (Barbato G, Moul DE, Schwartz PJ, Rosenthal NE, Oren DA, in press) ,rod foand the dopamine precursor, levodopa, to be no better than placebo in the treatment of SAD (Oren DA, Moul DE, Schwartz PJ, Wehr TA, Rosenthal NE, unpublished data, 1992). Insofar as there are many interactions between the serotonergic and dopaminergic systems (Cools 1974; Blandina et al 1988L it may not be necessary, however, to choose between these neurotransmitters in attempting to find the pathophysiological basis for SAD. Indeed, they might be disordered in concert with each other, and light therapy may influence both systems. S.nadies of the behavioral effects of m-CPP adminis~ation have previously been undertaken in patients with other conditions (Murphy et al 1991; Kahn and We~ler 199!), for example, panic disorder (Charney et al 1988; Kahn et
J.R. Joseph-Vanderpool et al
al 1988) obsessive compulsive disorder (Chamey et al 1988; Zohar et al 1987), schizophrenia (Seibyl et al 1991) and Alzheimer's d|sease (Lawlor et al 1989). Results have been variable, with some studies showing no difference between patients and normals. Other studies, however, have shown exacerbation of symptoms. Thus, panic-disorder patients developed panic attacks to a greater degree than controls (Kahn et al 1988); obsessive-compulsive disorder patients developed an exacerbation of obsessivecompulsive symptoms (Zohar et al 1987); schizophrenics became more psychotic (Seibyl et al 1991); and Alzheimer's disease patients became more forgetful (Lawlor et al 1989). Other, nonspecific effects were also noted following m-CPP administration in the above studies. Little work has been done e ~. the effects of m-CPP in nonseasonally depressed patients. In an acute study of oral mCPP administration, depressed patients did qot differ from controls with respect to effects on mood (Kahn et al 1990), whereas in a preliminary study using 2-week periods of drug administration, m-CPP appeared to lead to reduced levels of depression and anxiety in some patients (Mellow et al 1990). The very large increase in "'activation/euphoria'" reported by SAD patients in the winter appears to be somewhat specific to this group. Although healthy volunteers have reported increased self-ratings of "activation/euphoria" after m-CPP, these changes were considerably smaller and represented statistically significant changes only in large subject groups (Mueiler et al 1985; Murphy et al 1989). Seasonal variation in response to m-CPP has not previously been documented, but given the well-documented variation in serotonin metabolism in humans, one might expect to find seasonal variations in other groups. Thus, season of study should be regarded as a potential source of variance in this challenge paradigm, as in other tests of serotonergic function. Insofar as the responses of SAD patients and noL:m.a!controls to m-CPP infusions differed across seasons, the results of this study provide further evidence of dysregulation of serotonergic systems in SAD.
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