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Patients' weights were assessed during placebo-controlled, amitriptyline-controlled, and uncontrolled bupropion trials. Low-moderate (50-450 mg/day) to moderate-high (300-750 mg/day) doses of bupropion were consistently associated with a lack of weight gain (average weight loss of 1-2 pounds); placebo was associated with an average weight gain of 1 lb and 75-225 mg/day of amitriptyline was associated with an increase of 3-9 lb. Bupropion treatment was rarely accompanied by reports of appetite change and had no statistically significant effect on caloric intake when compared to placebo.

This study evaluated the effects of developmental protein malnutrition on the spontaneous electrical activity of frontal cortex neurons in the anesthetized rat. Rats were raised prenatally and postnatally on either an 8% or 6% casein diet until adulthood. Compared to the 25% casein controls, both malnourished groups showed a 30-36% decrease in mean discharge rates and a 100-200% increase in the percentage of cells with very slow (less than 1/s) discharge rates. Most of the diet-related changes were confined to a zone 600-1200 micron below the brain surface, approximately cortical layers III, IV and V. A second set of studies in which diet reversals were introduced at birth or in adulthood found that: (a) restoration of a normal 25% casein diet at birth did not appreciably attenuate the effect of prenatal administration of an 8% casein diet; (b) introduction in adulthood of the 8% casein diet to a normally fed rat had no effect; (c) introduction of the 8% diet at birth, however, produced effects in adulthood comparable to those seen when the protein malnutrition was introduced in the prenatal period. Thus, the rat brain is sensitive to both prenatal and postnatal protein malnutrition (starting at birth). Most importantly, the effects of prenatal protein malnutrition on the activity of frontal cortex neurons do not appear to be reversible by restoration of a normal diet in adulthood or at birth.

The cardiovascular profile of bupropion has been assessed in over 700 depressed patients. Most of the studies reviewed were double-blind comparisons with placebo or amitriptyline. Subjects included depressed adult outpatients without cardiovascular disease, elderly patients, and patients with cardiovascular disease. Increased heart rate was seen only with amitriptyline, which also caused a subclinical delay in cardiac conduction. Bupropion did not adversely affect supine or standing blood pressure, and patients with tricyclic-induced orthostatic hypotension did not show orthostasis when treated with bupropion. The incidence of subjective cardiovascular complaints with amitriptyline but not with bupropion exceeded that with placebo. Patients with cardiovascular disease who received bupropion had no change in heart rate or blood pressure compared to baseline; their incidence of cardiovascular complaints was comparable to that of disease-free controls. Finally, five patients who took large amounts of bupropion in suicide attempts showed no distinct cardiovascular abnormalities. Thus, bupropion appears safer than amitriptyline and other tricyclics in patients who are prone to orthostatic hypotension or cardiac conduction disorders, and may have a wider safety margin in overdose.

There is considerable evidence that the raphé system and the region of the nucleus tractus solitarious (NTS), including the area postrema, play significant roles in slow-wave sleep mechanisms and in EEG synchronization. Studies of the interactions between these systems and the neocortex are much needed. If neuronal activity in these lower brainstem regions regulates the degree of cortical synchrony then a high degree of correspondence between the EEG of the area postrema or raphé complex with that of the cortex might be expected. In order to quantitate the reequency characteristics of the EEG obtained from these subcortical sites (nucleus raphé dorsalis, area postrema, as well as anatomical controls adjacent to these regions) during the different vigilance states (waking, slow-wave sleep, REM sleep) in the cat, power spectral analyses techniques were employed. Comparison of these subcortical spectral characteristic with those obtained from cortical (frontal and occipital) sites during the same vigilance state, show that the spectral measures elicited from the region of the area postrema closely correspond to that of the cortex, particularly during slow-wave sleep. On the other hand, the EEG of the anterior portion of the raphé region, although exhibiting a substantial low frequency component during slow-wave sleep in comparison to wakefulness does not show a statistically significant shift to low frequencies such as occurs in the area postrema or the cortex. These results suggest that the increases in the low frequency content of the cortical EEG sites during slow-wave sleep results from synchronizing inputs from the area postrema to a greater extent than from the raphé complex.

Bupropion is a novel, structurally unique (single ring) compound, radically different from tricyclic antidepressants in its pharmacologic profile. In a random assignment, double-blind, long-term follow-up study of 60 depressed in- and outpatients (DSM-III criteria) in eight centers, the antidepressant actions of bupropion and amitriptyline were compared. Bupropion was as effective as amitriptyline in reducing depressive symptoms over a 6-month period, as measured by Hamilton depression and anxiety scales and Clinical Global Impression scores. Unlike amitriptyline, bupropion did not increase uric acid or cholesterol levels, and was not associated with weight gain. Bupropion was better tolerated than amitriptyline, the most commonly prescribed antidepressant.

Rats born of mothers fed a low protein diet (8% casein versus a normal 25% casein diet) starting 5 weeks prior to mating showed a 50-100% increase in protein synthesis in the brain and kidney on the day of birth. This effect was due to a 50-100% increase in the uptake of IP injected 14C-leucine in the malnourished rats. The proportion of total tissue radioactivity in the trichloroacetic acid-protein precipitates was the same in the 8% and 25% casein groups. For the most part, there were no significant diet related changes in uptake or incorporation of 14C-leucine in the brain, liver or kidney in the 8% and 25% casein groups on Days 5, 10-11 and 21. While the physiological basis of the diet related changes seen on the day of birth is unknown, the present data represent a previously undescribed effect of prenatal protein malnutrition.

Cats injected with LSD (d-lysergic acid diethylamide) exhibit a group of behaviors that appear to be specific to hallucinogenic drugs. Two of these behaviors, limb flick and abortive grooming, have an extremely low frequency of occurrence in normal cats, but often dominate the behavior of LSD-treated cats. The frequency of occurrence of this group of behaviors is related to the dose of LSD. The behavioral changes are long-lasting following a single injection of LSD, and exhibit tolerance following the repeated administration of LSD. They are not elicited by a variety of control drugs, but are elicited by other indole nucleus hallucinogens. Because the behavioral effects are specific, reliable, easy to score, and quantifiable, they represent an animal model that can be used in studies of the effects of LSD and related hallucinogens.

The effect of systemically administered morphine sulfate on the cortical EEG of the rat was studied using direct visual scoring procedures and spectral and amplitude distribution analysis techniques. The EEG effect was found to be dose-dependent, i.e., as higher doses of morphine were administered morphine-induced spindles or spike-like activity progressively increased and were eventually replaced by a highly synchronized EEG. In quantifying these EEG patterns, using spectral analysis, distinct frequency spectra were found for morphine-induced spindles and epochs of high voltage low frequency (HVLF) activity. The power in the 5-7 Hz frequency band was found to be a good indicator of the duration of the morphine effect since the value of this index was elevated during the time course of the drug effect. In addition, amplitude distribution methods revealed the sensitivity of two specific measures to the EEG changes induced by morphine. Values of standard amplitude followed closely the degree of EEG synchronization while kurtosis proved sensitive enough to follow the effect of specific doses of morphine sulfate.

The incidence of convulsions in patients receiving tricyclic antidepressants or bupropion was reviewed. For both types of drug, the risk of a seizure was dose-dependent and was higher in patients with predisposing factors, e.g., a history of seizures. Patients without a predisposing factor had a convulsion incidence of approximately 0.6%-0.9% (6-9/1,000 patients) when receiving imipramine at doses of greater than 200 mg/day or bupropion at doses greater than 450 mg/day. At lower doses, the frequency of seizures dropped to about 1/1,000 (or less) for imipramine and bupropion. Thus, the risk of a seizure in patients receiving equally therapeutic doses of imipramine and bupropion appears to be comparable.

We evaluated the anxiolytic property of a brain-specific gamma-aminobutyric acid delivery system (GABA-CDS) in male rats by means of a drink-foot shock conflict procedure. Brain-specific delivery of the active compound was achieved by combination of GABA benzyl ester with an interconvertible dihydropyridine in equilibrium pyridinium salt carrier, which is "locked in" to the brain upon its oxidation. Pharmacokinetic studies revealed that the hydrophilic pyridinium salt form (G-Q+) of the GABA-CDS formed in situ remained in the brain for 12 h but was cleared from the blood and other peripheral tissues by 0.5-4 h. While the lipophilic form (G-DH) of the GABA-CDS caused a marked and sustained anxiolytic response when administered systemically, GABA and the charged pyridinium salt (G-Q+ form) of the GABA-CDS were ineffective. G-DH was injected at either 0, 4, 10 or 25 mg/kg IV in DMSO after rats were water and food deprived. After either 0.5, 2, 4, 8 or 24 h, rats were permitted 10 s of shock-free drinking of 10% sucrose, then given a 35 mA (DC) current through the drinking tube. Drinking time was recorded for 3 min. All doses of G-DH caused a significant increase in anxiolysis over control levels through 8 h. An increase (4 to 7-fold) in anxiolytic activity was observed through the 10 mg/kg dose with the 25 mg/kg dose causing no additional increase. No sedation or analgesia was observed at 2 h with any anxiolytic-producing dose of G-DH. These results suggest that G-DH elicits anxiolysis with minimal sedation, through the local brain action the G-Q+ or subsequent to the release of GABA.

A placebo-controlled double-blind study was conducted to test the antidepressant effects of bupropion at dosage levels of 300 or 450 mg/day. Subjects were 30 hospitalized primary major depressives who were treated for 4 weeks. Physical and behavioral measures were obtained at baseline and at the end of each experimental week. The combined results of the two bupropion groups were significantly better than placebo. Preliminary results showed a significant antidepressant effect of the 300 mg/day dose, but not the 450 mg/day dose, compared to placebo. Anxiety symptoms were also somewhat reduced by the 300 mg/day dose. The results are compared with those of a previous study, which utilized higher dosages.

Horseradish peroxidase (HRP) has been widely used in neurobiology to trace neural pathways (axonal transport) and to correlate physiology with morphology (intracellular injection). We report that 5% HRP in 0.1 M phosphate buffered normal saline may be used to fill micropipettes for stable extracellular single cell recordings. HRP can then be iontophoresed at the desired recording site(s) and does not appear to impair activity of other neurons in the area or to cause damage to the electrode tip after the marking procedure. Subsequent perfusion, sectioning and reacting of the brain with the diamino-benzidine chromagen yielded a discrete (100-500 mu diameter) brown reaction product in the extracellular space, as well as peroxidase filled perikarya which were readily distinguishable from damaged vascular or neural elements. This method is highly reliable and provides a simple technique for localizing the tip of micropipette electrodes.

The general use of cyclodextrins in drug formulations is reviewed. The ability of cyclodextrins to form reversible inclusion complexes with many drugs can eliminate various undesirable physicochemical properties. While beta-cyclodextrin is extremely useful in many of these applications, it is toxic when given parenterally, precluding its use in i.v. and other formulations. Chemically modified cyclodextrins such as 2-hydroxypropyl-beta-cyclodextrin are amorphous isomeric mixtures which are potent complexing agents and innocuous when administered i.e., either acutely or subchronically. The use of these modified cyclodextrins in parenteral formulations and to solubilize and stabilize various proteins and peptides is presented.

Four experiments were performed to evaluate the effects of developmental protein deprivation on the behavioral response of adult rats to treatments known to affect central nervous system catecholamine systems. Results showed no group differences between protein malnourished and control animals in locomotor responsiveness to d- or l-amphetamine, recovery from behavioral asymmetry produced by a unilateral lesion of the substantia nigra, or in the development of response patterns indicative of denervation supersensitivity. However, a dose-dependent diminution in the ability of apomorphine to produce stereotyped behavior was noted in the malnourished group, suggesting that a class of brain dopamine receptors may be impaired or may have undergone homeostatic modification as a result of the undernutrition procedure.

During the clinical development of bupropion (Wellbutrin) 1,153 depressed patients and 157 normal volunteers received bupropion (doses, 15-1200 mg/day); 177 placebo-treated and 196 tricyclic-treated patients (doses, 25-300 mg/day) also participated in these trials to provide a control comparison. Safety measures during the clinical trial program included adverse event symptomatology, vital signs, clinical laboratory examinations, and EEGs. There were no bupropion-related changes in vital signs, clinical laboratory, or EEG results severe enough to warrant treatment discontinuation. The most common cause for discontinuation in the bupropion (9.1%), placebo (6.8%), and tricyclic groups (9.2%) was agitation/excitement. The only adverse experience considered of medical significance in bupropion patients was major motor seizure. The incidence of a seizure was less than 1 per 1,000 at usual outpatient doses and less than 1 per 100 at usual inpatient doses. These incidences appear to be comparable to those seen with equally therapeutic doses of tricyclic antidepressants.

Spontaneous neuronal activity was recorded extracellularly from isolated single units in frontal neocortex and caudate nucleus of young and aged F344 rats anesthetized with urethane. Average firing rates, mean interspike intervals (ISI) +/- standard deviations, and ISI frequency histograms were computed and analyzed by microprocessor. For frontal cortex cells (N = 226), there was a nonsignificant trend toward slower average discharge rates in the old group. However, a significantly longer mean ISI and proportionally more very slow firing cells (less than 1 Hz) were observed in old rats. A laminar analysis of frontal cortex unit activity in young animals showed average discharge rates to be distributed somewhat evenly throughout the cortical mantle with the exception of the zone 1200-1400 mu beneath brain surface. This depth corresponds approximately to layer V where a 50% increase in mean firing rate in young animals was observed. In aged animals, this increased cell firing in layer V was absent, while mean discharge rates in other laminae remained essentially the same in the young and old rat groups. Caudate nucleus cells (n = 70) showed a significant shift towards fewer fast discharging cells in old rats, with the average firing rate diminished by one-third. Although more brain regions need to be examined in a similar fashion, the consistency of the present results with those previously reported for the brainstem and cerebellum suggests that slower firing rates and longer ISIs are likely to be wide-spread throughout the brains of aged rats.

Available evidence is reviewed concerning the antidepressant efficacy of bupropion in patients who had failed to respond to or been unable to tolerate tricyclic antidepressants (TCAs) during prior episodes of depression. Inpatients classified as TCA nonresponders were randomly assigned to double-blind treatment with bupropion (N = 19) or placebo (N = 11). Patients receiving bupropion showed an excellent antidepressant response, whereas those receiving placebo showed minimal improvement (p less than .001). Inpatients who were classified as TCA responders responded well to double-blind treatment with bupropion, but also had a substantial, although significantly smaller (p less than .05), response to placebo. Outpatients (N = 33) with a history of nonresponse or nonresponse plus intolerance to TCAs showed marked improvement during open treatment with bupropion. The results from both double-blind and open treatment with bupropion demonstrate that this drug offers a promising alternative therapy for patients with a history of poor response to TCAs.

Body weight and appetite were evaluated in 40 depressed outpatients from a private psychiatric practice who were receiving low-modest doses of tricyclic antidepressants. Amitriptyline (maximum of 150 mg/day), nortriptyline (maximum of 50 mg/day), and imipramine (maximum of 80 mg/day) were given for an average of 6 months of treatment. There was a mean weight increase of 1.3-2.9 lbs/month, which led to an average total weight gain of 3-16 lbs, depending on drug, dose and duration. These weight increases were linear over time and were accompanied by marked increases in the preference for sweets. Ultimately, excessive weight gain was the most common cause of discontinuation of treatment, occurring in one-half of the patients. Significant weight loss occurred upon discontinuation of drug. These findings show that chronic administration of low-modest doses of tricyclic antidepressants frequently cause considerable weight gain and can significantly interfere with the ability to provide long-term maintenance therapy.

Sixty female and male outpatients with psychosexual dysfunction (sexual aversion/inhibited sexual desire, inhibited sexual excitement, and/or inhibited orgasm) participated in a comparison of the efficacy of bupropion hydrochloride vs placebo. Eight weeks of single-blind treatment with placebo was given at the outset to establish a baseline of sexual ratings/behavior and to eliminate placebo responders. Patients were then assigned randomly to 12 weeks of double-blind treatment with bupropion, 225-450 mg/day, or matching placebo. The onset of therapeutic sexual effects was gradual, but by the end of 12 weeks of treatment, significantly greater improvements were noted on the libido and global assessments of sexual functioning in the bupropion group. Sixty-three percent of the bupropion-treated patients reported themselves much or very much improved, compared with 3% for placebo. Changes in the frequency of sexual behavior, however, were much less dramatic and consisted largely of trends toward more sexual activity. To our knowledge, these results represent the first demonstration in a well-controlled clinical trial of an improvement in the psychological aspects of sexual dysfunction due to pharmacologic treatment.

Patients who developed clinically significant and documented orthostatic hypotension during treatment with tricyclic antidepressants were withdrawn from the tricyclic for at least 5 days. During a baseline period of 3-7 days a placebo identical to bupropion was then administered. A baseline electrocardiogram, psychiatric scale ratings, vital signs, clinical laboratory and physical exam were performed on those patients on placebo who were free of orthostatic hypotension for 3 consecutive days. Patients were then transferred to an ascending dosage regimen of bupropion. Only patients who were treated with bupropion for at least 7 days and who received a daily dose of at least 450 mg were considered to have completed the study. The results in 12 inpatients in 2 centers showed that bupropion produced no clinically significant alterations in pulse rate, systolic blood pressure or orthostasis as compared to placebo in patients who had clinically significant orthostatic hypotension caused by tricyclic treatment.

Studies were carried out on the trans-callosal evoked response in rats born of dams fed either a low (8%) or normal (25%) protein diet beginning 5 weeks prior to mating and throughout gestation and lactation. After weaning, pups were fed the same diets as their mothers. Bipolar (surface vs depth) stainless steel stimulating and recording electrodes were positioned at corresponding loci in the right and left sensorimotor cortices. Trans-callosal evoked responses were measured under urethane anesthesia using twice-threshold bipolar pulses of .1 msec duration at ages 13, 21, and 60-66 days. Evoked response latency was significantly greater in malnourished animals at 13 days of age, whereas at adulthood no latency differences were seen. Poststimulation excitability (15-100 msec range) was not significantly affected by the dietary treatment. These results are interpreted as corroborating previous reports on rats undernourished during development using sensory evoked potentials. By avoiding the use of extrinsic sensory stimulation, the present study demonstrates a dietary effect upon ontogeny of cortical evoked potentials independent of any possible effect on sensory receptor mechanisms.

The uptake of intraperitoneally injected 125I-labeled rat growth hormone into brain and peripheral tissues was measured in normal and hypophysectomized adult rats. A significant level of radioactivity was observed in the seven brain regions examined -- the telencephalon, diencephalon, midbrain, pons-medulla, cerebellum, pineal and pituitary glands. The pineal and pituitary glands, which are outside the blood-brain barrier, contained three to four times the concentration of radioactivity of the other brain regions. Compared to brain, the level of radioactivity was much higher in peripheral tissues (the diaphragm, kidney, serum and liver). For example, the serum contained ten times the level of radioactivity of most brain regions. For a given tissue, however, the normal and hypophysectomized rats showed a comparable amount of 125I-growth hormone. Trichloroacetic acid precipitates from each tissue sample showed that peripheral tissues had a higher proportion of radioactivity (35-48% of total tissue radioactivity) than the brain samples (13-26%). The data support the view that growth hormone, or a metabolite can enter the central nervous system and may directly affect on-going metabolic processes.

A critical review of the evidences relating the biogenic amines serotonin and norepinephrine to the states of slow-wave and rapid eye movement (REM) sleep is presented. Various alternative explanations for specific chemical regulation of the individual sleep states, including the phasic events of REM sleep, are evaluated within the overall framework of the monoamine theory of sleep. Several critical neuropsychopharmacological studies relating to metabolsim of the amines in relation to sleep-waking behavior are presented. Models of the chemical neuronal circuitry involved in sleep-waking activity are derived and interactions between several brainstem nuclei, particularly the raphé complex and locus coeruleus, are discussed. Activity in these aminergic systems in relation to oscillations in the sleep-waking cycles is evaluated. In particular, the assessment of single cell activity in specific chemical systems in relations to chemical models of sleep is reviewed. Overall, it appears that the biogenic amines, especially serotonin and norepinephrine, play key roles in the generation and maintenance of the sleep states. These neurotransmitters participate in some manner in the "triggering" processes necessary for actuating each sleep phase and in regulating the transitions from sleep to waking activity. The biogenic amines are, however, probably not "sleep factors" or direct inducers of the sleep states. Rather, they appear to be components of a multiplicity of interacting chemical circuitry in the brain whose activity maintains various chemical balances in different brain regions. Shifts in these balances appear to be involved in the triggering and maintenance of the various states comprising the vigilance continuum.

The characteristics of the spontaneous discharges of populations of single neurons in the neocortex and thalamus of rats reared under chronic protein malnutrition (8% casein) or a normal diet (25% casein) were evaluated. Results from 700 neurons showed the malnourished rats had fewer fast firing cells, an overall lower discharge rate and an altered firing pattern (fewer cells which exhibited bursting activity). These findings are the first demonstration of altered neuronal discharges in the forebrains of adult malnourished rats.

Sleep-waking profiles were obtained from 130 7 hr stimulation-EEG recording sessions in a series of cats bearing chronically implanted stimulating electrodes in the regions of the area postrema and anterior raphe nuclei. The results indicated that: (a) during electrical stimulation of the region of the area postrema with 0.5 or 10 Hz at 1 and 2 mA there were significant increases in the occurrence of the deeper aspects of slow-wave sleep and in REM sleep. These elevations were significant in comparison to nonstimulation baselines and to sleep profiles obtained during stimulation of points located dorsal and anterior to the area postrema. (b) Stimulation of the medial reticular formation including the anterior raphe using the same parameters employed for the area postrema did not alter the occurrence of any stage of sleep. These findings indicate that the region of the area postrema may be more involved in the generation of sleep than the anterior raphe nuclei.

In the course of examining the complete dose-response relationship for the behavioral effects of LSD in the cat, we discovered that, in addition to large increases in investigatory and hallucinatory-like responses, two behaviors, not previously reported, are emitted with a high probability under LSD. Beginning from a baseline of essentially zero in saline-treated animals, limb flicks and abortive grooming increase in frequency in direct relation to the dose of LSD administered (2.5, 10, 25 and 50 microgram/kg i.p.) and then decrease at higher doses (100 and 200 microgram/kg). Limb flicks are a species-specific behavior seen in normal cats almost exclusively in response to the presence of a foreign substance, such as water, on the hindpaw or forepaw. In abortive grooming, the cat orients to the body surfaces as if to groom but does not emit the consummatory grooming response (bite, lick or scratch), or emits the response in midair. These behaviors can serve as an animal behavior model for the actions of LSD and related hallucinogens in humans. The specificity of these behavioral changes is indicated by the fact that they are never seen in response to other classes of psychoactive drugs such as D-amphetamine, atropine, caffeine, and cholorpheniramine. They are, however, elicited by compounds such as psilocybin which are structurally and functionally related to LSD. The validity of the model is based on evidence indicating that it is: specific to hallucinogens, dose dependent, observed in a dose range effective in humans, parallels the major parameters of the actions of LSD in humans (see following paper), sensitive, robust, reliable, quantifiable and easy to score.

The effects of IP administered bovine growth hormone (GH) on regional brain serotonin, 5-hydroxyindoleacetic acid (5-HIAA) and norepinephrine levels in rats were examined. GH decreased the levels of both monoamines and 5-HIAA in the diencephalon and brainstem while not affecting telencephalic concentrations. In hypophysectomized rats, however GH produced significant elevations of monoamine and 5-HIAA levels in all brain regions. In normal rats the decreases in norepinephrine content produced by GH were correlated with a reduction in the stimulatory action of d-amphetamine on general activity levels. These results demonstrate that GH can affect brain biogenic amines and that these effects have behavioral consequences.

Recent studies of afferent connections of the anterior raphe using the horseradish peroxidase technique have demonstrated a major projection originating in the substantia nigra (SN). The present acute electrophysiological study examined the influence of stimulation of the afferent on the activity of individual neurons in the raphe of the posterior midbrain and anterior pons (n = 51), and of a control group of cells (n = 15) located 2 mm lateral to the raphe. The predominant effect of SN stimulation at 0.1-1.0 mA, 1 Hz or 10 Hz, was suppression of raphe activity, with 63% of the cells showing cessation of firing following SN pulses and only 8% showing excitation. The average duration of suppression was 200 msec at 1 Hz and 38 msec at 10 Hz. In contrast, 40% of the lateral cells were excited, with 27% of the cells showing suppression. The mean duration of total suppression of lateral cell firing was 61 and 17 msec at 1 and 10 Hz, respectively. The results from the raphe cells are consistent with recent reports of stimulation of other forebrain and brainstem afferents to the raphe in which suppression of raphe activity was the main effect.

Bupropion HCl, a new nontricyclic antidepressant, produced marked improvement in 49 hospitalized patients with primary depression at doses of 300-600 mg/day. Bupropion resulted in statistically significant differences from placebo as early as day 5, and by the end of the 4-week study 79% (N = 27) of the bupropion patients and 13% (N = 2) of the placebo patients showed much to very much improvement. Bupropion and placebo had similar side effect profiles. Tremor and sweating were reported more often with bupropion and headache, nausea, and tiredness with placebo.