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This chapter focuses on several different research strategies, to characterize the clinical and biological nature of panic disorder. It explores new data regarding the phenomenological and longitudinal features of the disorder are presented. The chapter describes biological and psychophysiologic correlates of anxiety are reviewed in relation to research from our laboratory investigating the sleep architecture, pain perception, glucose metabolism and platelet receptor function in patients with panic disorder. It discusses the data from the pharmacologic challenges in humans with clonidine, yohimbine, and caffeine are discussed within the context of current biological theories of anxiety. Agoraphobia with panic attacks is an anxiety syndrome complicated frequently by the presence of depression. Preliminary data from the sleep laboratory suggest that panic patients may have increased motor activity during the sleep.

Objective: To compare the efficacy and tolerability of tranylcypromine vs. lamotrigine in bipolar depression not responding to conventional antidepressants.Method: Bipolar depressed patients received open randomized treatment with tranylcypromine or lamotrigine as add-on to a mood stabilizer during 10 weeks. In a second treatment phase, non-responding patients could receive the opposite drug. Outcome criteria were response (measured with CGI-BP and IDS-C), switch into mania, and completion of the study.Results: Only 20 of 70 planned patients were randomized, due to problems with recruitment, and 19 patients received any medication. During the first treatment phase 5/8 patients (62.5%) responded to tranylcypromine without switch into mania, compared with 4/11 patients (36.4%) on lamotrigine with two switches (statistically not significant). Over both treatment phases, 8/10 patients (80%) receiving tranylcypromine completed the study vs. 5/13 (38.5%) on lamotrigine (likelihood 0.02).Conclusions: There still appears to be a role for tranylcypromine in the treatment of refractory bipolar depression. Larger controlled studies are demanded.

BackgroundFew studies have examined the relative risks of switching into hypomania or mania associated with second-generation antidepressant drugs in bipolar depression.AimsTo examine the relative acute effects of bupropion, sertraline and venlafaxine as adjuncts to mood stabilisers.MethodIn a 10-week trial, participants receiving out-patient treatment for bipolar disorder (stratified for rapid cycling) were randomly treated with a flexible dose of one of the antidepressants, or their respective matching placebos, as adjuncts to mood stabilisers.ResultsA total of 174 adults with bipolar disorder I, II or not otherwise specified, currently in the depressed phase, were included. All three antidepressants were associated with a similar range of acute response (49–53%) and remission (34–41%). There was a significantly increased risk of switches into hypomania or mania in participants treated with venlafaxine compared with bupropion or sertraline.ConclusionsMore caution appears indicated in the use of venlafaxine rather than bupropion or sertraline in the adjunctive treatment of bipolar depression, especially if there is a prior history of rapid cycling.

BackgroundThe Stanley Foundation Bipolar Network (SFBN) was created to address the paucity of help studies in bipolar illness.AimsTo describe the rationale and methods of the SFBN.MethodThe SFBN includes five core sites and a number of affiliated sites that have adopted consistent methodology for continuous longitudinal monitoring of patients. Open and controlled studies are performed as patients' symptomatology dictates.ResultsThe reliability of SFBN raters and the validity of the rating instruments have been established. More than 500 patients are in continuous daily longitudinal follow-up. More than 125 have been randomised to one of three of the newer antidepressants (bupropion, sertraline and venlafaxine) as adjuncts in a study of mood stabilisers and 93 to omega-3 fatty acids. A number of open clinical case series have been published.ConclusionsWell-characterised patients are followed in a detailed continuous longitudinal fashion in both opportunistic case series and double-blind, randomised controlled trials with reliable and validated measures.

Background Development of manic symptoms on antidepressant discontinuation has primarily been reported in unipolar patients. This case series presents preliminary evidence for a similar phenomenon in bipolar patients. Method Prospectively obtained life chart ratings of 73 bipolar patients at the National Institute of Mental Health were reviewed for manic episodes that emerged during antidepressant taper or discontinuation. Medical records were utilized as a corroborative resource. Six cases of antidepressant discontinuation-related mania were identified and critically evaluated. Results All patients were taking conventional mood stabilizers. The patients were on antidepressant treatment a mean of 6.5 months prior to taper, which lasted an average of 20 days (range, 1-43 days). First manic symptoms emerged, on average, 2 weeks into the taper (range, 1-23 days). These 6 cases of antidepressant discontinuation-related mania involved 3 selective serotonin reuptake inhibitors (SSRIs), 2 tricyclic antidepressants (TCAs), and 1 serotonin-norepinephrine reuptake inhibitor. Mean length of the ensuing manic episode was 27.8 days (range, 12-49 days). Potential confounds such as antidepressant induction, phenomenological misdiagnosis of agitated depression, physiologic drug withdrawal syndrome, and course of illness were carefully evaluated and determined to be noncontributory. Conclusion These 6 cases suggest a paradoxical effect whereby antidepressant discontinuation actually induces mania in spite of adequate concomitant mood-stabilizing treatment. These preliminary observations, if replicated in larger and controlled prospective studies, suggest the need for further consideration of the potential biochemical mechanisms involved so that new preventive treatment approaches can be assessed.

Anticonvulsants have moved into an important position as alternatives and adjuncts to lithium carbonate in the treatment of bipolar illness. Work with the nonhomologous model of kindled seizures helped in the choice of carbamazepine as a potential mood stabilizer and in the study of the mechanisms of action of the second generation anticonvulsants carbamazepine and valproate, as well as the putative third generation psychotropic anticonvulsants lamotrigine and gabapentin. Anticonvulsant neuropeptides such as TRH and nonconvulsant approaches with repeated transcranial magnetic stimulation (rTMS) also appear promising.

Kindling involves repeated administration of brief high-frequency electrophysiological stimulation of the brain at initially subthreshold intensities that eventually evoke full-blown seizures. It has thus been used not only as a model of epileptogenesis, but of long-term neuronal memory. Quenching is a phenomenon that utilizes low-frequency stimulation for much longer periods of time (eg, 1 Hz for 15 minutes), and appears to exert preventive effects on the development of kindling and inhibit the manifestation of full-blown kindled seizures by markedly increasing the amygdala afterdischarge and seizure threshold. (See also “Kindling and Quenching: Conceptual Implications for rTMS,” by Weiss and Post, page 32). The parameters of kindling and quenching with intracerebral stimulation of the amygdala in vivo are highly similar to those achieved in vitro in hippocampai slice preparations for inducing long-term potentiation (LTP) and longterm depression (LTD), respectively. These neuroplastic changes are relatively long lasting and appear reversible at the level of synaptic function with either LTD or LTP capable of countering the effects of the other.

With the increasing recognition of lithium's inadequacy as an acute and prophylactic treatment for many patients and subtypes of bipolar illness, the search for alternative agents has centered around the mood stabilizing anticonvulsants carbamazepine and valproate. In many instances, these drugs are effective alone or in combination with lithium in those patients less responsive to lithium monotherapy, including those with greater numbers of prior episodes, rapid-cycling, dysphoric mania, co-morbid substance abuse or other associated medical problems, and patients without a family history of bipolar illness in first-degree relatives. Nineteen double-blind studies utilizing a variety of designs suggest that carbamazepine, or its keto-congener oxcarbazepine, is effective in acute mania; six controlled studies report evidence of the efficacy of valproate in the treatment of acute mania as well. Fourteen controlled or partially controlled studies of prophylaxis suggest carbamazepine is also effective in preventing both manic and depressive episodes. valproate prophylaxis data, although based entirely on uncontrolled studies, appear equally promising. Thus, both drugs are widely used and are now recognized as major therapeutic tools for lithium-nonresponsive bipolar illness. The high-potency anticonvulsant benzodiazepines, clonazepam and lorazepam, are used adjunctively with lithium or the anticonvulsant mood stabilizers as substitutes or alternatives for neuroleptics in the treatment of manic breakthroughs. Preliminary controlled clinical trials suggest that the calcium channel blockers may have antimanic or mood-stabilizing effects in a subgroup of patients. A new series of anticonvulsants has just been FDA-approved and warrant clinical trials to determine their efficacy in acute and long-term treatment of mania and depression. Systematic exploration of the optimal use of lithium and the mood-stabilizing anticonvulsants alone and in combination, as well as with adjunctive antidepressants, is now required so that more definitive treatment recommendations for different types and stages of bipolar illness can be more strongly evidence based.

The objective of this study was to assess the psychiatric effects of the antiepileptic drug (AED) felbamate (FBM) in patients with epilepsy. FBM is a new AED with a novel putative (antiglutaminergic) mechanism. Older AEDs such as carbamazepine and valproate have psychotropic properties, but the psychiatric effects of FBM and other new antiglutamatergic AEDs remain to be determined. Thirty inpatients with refractory epilepsy were openly tapered off all AEDs in conjunction with intensive presurgical monitoring prior to a two week randomized double-blind parallel trial of FBM monotherapy versus placebo, followed by open FBM therapy. Psychopathology was rated with weekly psychiatric rating scales. Anxiety, depression and seizures increased significantly with AED discontinuation. Acute blind FBM monotherapy yielded antiepileptic and stimulant-like effects (insomnia, anorexia, and anxiety), but failed to influence AED withdrawal-emergent psychopathology. Restarting original AEDs resolved such pathology in FBM drop outs. Chronic open FBM also had stimulant-like effects, with half of the patients displaying psychiatric deterioration and the other half modest improvement compared to baseline therapies. Baseline insomnia and anxiety may be markers for poorer psychiatric responses to chronic open FBM. FBM had stimulant-like effects, lacked anxiolytic effects, and failed to attenuate AED withdrawal-emergent psychopathology. Baseline insomnia or anxiety may predict poorer psychiatric responses to FBM. Further studies are required to assess whether the novel psychiatric effects observed with FBM also occur with other new antiglutamatergic AEDs.

The Stroop interference test requires a person to respond to specific elements of a stimulus while suppressing a competing response. Previous positron emission tomography (PET) work has shown increased activity in the right anterior cingulate gyrus during the Stroop test. It is unclear, however, whether the anterior cingulate participates more in the attentional rather than the response selection aspects of the task or whether different interference stimuli might activate different brain regions. We sought to determine (1) whether the Stroop interference task causes increased activation in the right anterior cingulate as previously reported, (2) whether this activation varied as a function of response time, (3) what brain regions were functionally linked to the cingulate during performance of the Stroop, and (4) whether a modified Stroop task involving emotionally distracting words would activate the cingulate and other limbic and paralimbic regions. Twenty-one healthy volunteers were scanned with H2 (15) O PET while they performed the Stroop interference test (standard Stroop), a modified Stroop task using distracting words with sad emotional content (sad Stroop), and a control task of naming colors. These were presented in a manner designed to maximize the response selection aspects of the task. Images were stereotactically normalized and analyzed using statistical parametric mapping (SPM). Predictably, subjects were significantly slower during the standard Stroop than the sad Stroop or the control task. The left mideingulate region robustly activated during the standard Stroop compared to the control task. The sad Stroop activated this same region, but to a less significant degree. Correlational regional network analysis revealed an inverse relationship between activation in the left mideingulate and the left insula and temporal lobe. Additionally, activity in different regions of the cingulate gyrus correlated with performance speed during the standard Stroop. These results suggest that the left midcingulate is likely to be part of a neural network activated when one attempts to override a competing verbal response. Finally, the left midcingulate region appears to be functionally coupled to the left insula, temporal, and frontal cortex during cognitive interference tasks involving language. These results underscore the important role of the cingulate gyrus in selecting appropriate and suppressing inappropriate verbal responses. © 1994 Wiley-Liss, Inc.

Successive episodes of affective illness often show an accelerating frequency of recurrence. Two very different preclinical models (behavioral sensitization to psychomotor stimulants and electrophysiological kindling) may be used as indirect analogies or non-homologous models for conceptualizing mechanisms underlying the progressive and evolving aspects of manic-depressive illness. These models focus on phenomena involved in the longitudinal course of illness and on novel treatment implications. Literature is reviewed on the acute and long-term effectiveness of the anti-convulsant carbamazepine, particularly in treatment of lithium-refractory bipolar illness. Potential mechanisms of carbamazepine's acute anticonvulsant and antinociceptive and delayed psychotropic actions are discussed. alpha-2 adrenergic and peripheral-type benzodiazepine receptors, and stabilization of type-2 sodium channels are likely involved in the anticonvulsant effects of carbamazepine. GABAB mechanisms are thought to be related to the antinociceptive but not anticonvulsant or psychotropic effects of carbamazepine. A large number of neurotransmitters remain candidates for the psychotropic effects and a novel animal model requiring chronic administration of carbamazepine in order to show efficacy is reported (Weiss et al., 1989). It is hoped that further understanding of the mechanism of action of the anti-convulsant agents in comparison and contrast with traditional psychotropic agents will help in generating new treatments and in uncovering the basic defects of manic-depressive illness.

Context: The prevalence of depressive symptoms co-occurring with hypomanic symptoms has not been quantified. Whether there is a greater likelihood for women to experience mixed symptoms has not been resolved. Objectives: To determine whether mixed hypomania is observed more frequently than euphoric hypomania and whether a sex effect exists in patients with bipolar disorder. Setting: Academic research settings in the United States (4 sites) and Europe (3 sites). Participants: Subjects were enrolled in a naturalistic prospective study after providing written informed consent. Main Outcome Measures: Mixed hypomania was defined at a given visit as a Young Mania Rating Scale score of 12 or higher and an Inventory of Depressive Symptomatology-Clinician-Rated Version score of 15 or higher. Given partial overlap of items from these scales, exploratory analyses were completed assessing instrument overlap affecting the findings. Results: In 908 patients, 14 328 visits over 7 years were evaluated. Patients with bipolar I disorder were significantly more likely to experience hypomania than those with bipolar 11 disorder. Of all 1044 visits by patients with hypomanic symptoms, 57% met criteria for mixed hypomania. The likelihood of depression was significantly greater for women during hypomania (P Conclusions: Mixed hypomania is common in patients with symptoms of hypomania and particularly common in women. Potential overlap of clinical symptom scales should be assessed before study of patients with bipolar disorder symptoms is undertaken.

Objectives: Anticonvulsants have provided major treatment advances for patients with bipolar disorder. Many of these drugs, including several with proven efficacy in bipolar mania or depression, enhance the activity of the gamma-amino butyric acid (GABA) neurotransmitter system. A new anticonvulsant, tiagabine, has selective GABAergic activity and is approved for patients with partial epilepsy. Few reports of its potential effectiveness in bipolar disorder, however, have been published. We sought to evaluate the effectiveness of tiagabine added to ongoing medication regimens in patients with bipolar disorder inadequately responsive to or intolerant of usual treatments. Methods: Seventeen treatment-refractory patients participating in the Stanley Foundation Bipolar Network (SFBN) long-term follow-up study were offered open treatment with add-on tiagabine after discussion of the risks, benefits, other treatment options and giving informed consent. Patients' clinical symptoms and somatic complaints were closely monitored with SFBN longitudinal and cross-sectional ratings. Four patients discontinued low-dose tiagabine prior to the second visit and were excluded from data analysis. Results: Thirteen patients received a mean of 38 days of treatment at a mean dose of 8.7 mg/day of tiagabine. On the Clinical Global Impression Scale for Bipolar Disorder Overall category, three (23%) patients showed much or very much improvement and 10 (77%) patients showed no change or worsening. Three significant adverse events were noted, including two presumptive seizures. Conclusions: Open add-on tiagabine for treatment-refractory patients with bipolar disorder demonstrated limited efficacy with the majority of patients showing no change or worsening of clinical symptoms. In addition, patients experienced serious side-effects attributed as likely due to the medication, which resolved without lasting consequence when tiagabine was discontinued.

Background. Systematic and accurate depiction of a patient's course of illness is crucial for assessing the efficacy of maintenance treatments for bipolar disorder. This need to rate the long-term prospective course of illness led to the development of the National Institute of Mental Health prospective Life Chart Methodology (NIMH-LCMTM-p or LCM). The NIMH-LCMTM-p allows for the daily assessment of mood and episode severity based on the degree of mood associated functional impairment. We have previously presented preliminary evidence of the reliability and validity of the LCM, and its utility in clinical trials. This study is a further and more extensive validation of the clinician rated NIMH-LCMTM-p.Methods. Subjects included 270 bipolar patients from the five sites participating in the Stanley Foundation Bipolar Network. Daily prospective LCM ratings on the clinician form were initiated upon entry, in addition to at least monthly ratings with the Inventory of Depressive Symptomatology-clinician rated (IDS-C), the Young Mania Rating Scale (YMRS) and the Global Assessment of Functioning (GAF). We correlated appropriate measures and time domains of the LCM with the IDS-C, YMRS and GAF.Results. Severity of depression on the LCM and on the IDS-C were highly correlated in 270 patients (r = −0·785, P < 0·001). Similarly, a strong correlation was found between LCM mania and the YMRS (r = 0·656, P < 0·001) and between the LCM average severity of illness and the GAF (r = −0·732, P < 0·001).Conclusions. These data further demonstrate the validity and potential utility of the NIMH- LCMTM-p for the detailed daily longitudinal assessment of manic and depressive severity and course, and response to treatment.

This investigation evaluated the relationship between changes in thyroid indices and mood stability during lithium and carbamazepine prophylaxis for bipolar disorder.In the first 2 years, 30 patients with bipolar mood disorder were randomly assigned to 1 year of lithium and then 1 year of carbamazepine, or vice versa; in the third year, they received lithium plus carbamazepine. By stepwise regression analysis, the degree and timing of lithium- and carbamazepine-induced thyroid changes and their subsequent relationship to long-term mood stability were evaluated.During the lithium phase, there was a significant inverse relationship between morbidity and mean serum level of free T4, i.e., a lower mean serum level of free T4 was associated with more affective episodes and greater severity of depression as shown by the Beck Depression Inventory. During the carbamazepine phase, there was an inverse relationship between mean level of total T4 and global severity rating. During the combination phase, no relationships between thyroid indices and clinical outcome were significant.In the lithium phase, a low level of free T4 was associated with more affective episodes and greater severity of depression. Whether this mood instability is causally related to low free T4 levels and whether it can be attenuated with T4 replacement remain to be studied in a controlled setting.

The systemic administration of thyrotropin-releasing hormone (TRH) to rats elicits locomotor activation, wet dog shakes, jaw movements, paw licking and tail rattle. Central dopamine (DA) and 5-hydroxytryptamine (5-HT) systems and peripheral vagal afferents have been implicated in these responses. To define this circuitry further, the effects of lesions of these pathways on the behavioral responses elicited by intraperitoneal (IP) injections of TRH were assessed in rats. Lesions of the DAergic innervation of the nucleus accumbens did not affect the locomotor activation, wet dog shakes, paw licking, jaw movements or tail rattle elicited by TRH. This is consistent with our in vivo microdialysis finding that TRH did not affect the release of DA in the nucleus accumbens at a dose that strongly increased locomotor activity. Depletion of spinal 5-HT significantly decreased the wet dog shakes induced by TRH, while depletion of forebrain 5-HT had no effect on any behavior. Bilateral vagotomy did not affect the locomotor response to TRH or any of the other behaviors measured. Taken together, these results suggest that the DAergic mesolimbic, the 5-HTergic projections to the forebrain and vagal afferent systems are not mediators of the behavioral responses to systemic TRH. In contrast, the raphe-spinal 5-HTergic projection system may serve to modulate the wet dog shakes elicited by this peptide.

Functional neuroimaging studies have found abnormal anterior cingulate activity in depressed subjects, and other studies have shown that the cingulate gyrus becomes active in healthy subjects during interference tasks. The authors hypothesized that subjects with mood disorder might show blunted cingulate activation during the standard Stroop interference task or during a modified version involving sadness-laden words. In contrast to 11 age- and sex-matched healthy control subjects who activated the left cingulate during the standard Stroop, 11 mood-disordered subjects activated the right anterior cingulate gyrus only slightly and instead showed increased activity in the left dorsolateral prefrontal and visual cortex. This study supports theories of blunted limbic and paralimbic activation and abnormal cingulate activity in depression and adds to the growing knowledge of the functional neuroanatomy of depression.

Rapid-rate transcranial magnetic stimulation (rTMS) was administered to 10 healthy volunteers on different days over the right or left prefrontal cortex, midfrontal cortex, occipital cortex, or cerebellum. Mood (self-rated), reaction time, and hormone levels were serially measured. Consistent with a previous study, comparison of hemispheres revealed significant associations with decreased happiness after left prefrontal rTMS and decreased sadness after right prefrontal rTMS. Stimulation of all three prefrontal regions, but not the occipital or cerebellar regions, was associated with increases in serum thyroid-stimulating hormone. There was no effect on serum prolactin. rTMS applied to prefrontal cortex is safe and well tolerated and produces regionally and laterally specific changes in mood and neuroendocrine measures in healthy adults. rTMS is a promising tool for investigating prefrontal cortex functions.

This retrospective single-case study demonstrates the development of tolerance and reresponse to carbamazepine in a patient with coexisting trigeminal neuralgia and manic-depressive illness. After an initial positive response, tolerance to the antinociceptive and psychotropic effects of carbamazepine appeared during treatment, despite increasing doses. As in preclinical studies of contingent tolerance, periods of carbamazepine discontinuation were associated with reresponse following reinstitution. These are the first clinical data interpreted in a contingent tolerance formulation with reresponse following a medication-free interval. Controlled and prospective studies are needed of the reliability and the pathophysiological and therapeutic implications of this phenomenon.

In view of the increasing use of lithium-carbamazepine combination therapy for refractory psychiatric disorders, the authors assessed the clinical laboratory effects of adding lithium to carbamazepine in 23 patients with affective disorders. Lithium produced a robust reversal of carbamazepine-induced leukopenia, increasing WBCs, predominantly neutrophils, to levels significantly above placebo baseline values. The combination produced additive antithyroidal effects, resulting in greater decreases in T4 and free T4 than with carbamazepine alone; the addition of lithium was associated with the emergence of a modestly higher TSH level. The authors discuss clinical and theoretical implications of these findings.

tion body mass index (BMI) categories: underweight 5 BMI , 18.5, normal weight 5 18.5–24.9, overweight 5 25.0–29.9, class I obese 5 30.0–34.9, class II obese 5 35.0–39.9, class III obese .39.9. Depressive and anxiety symptoms were gauged by respondents’ reports of the number of days in the last 30 days in which they felt sad, blue, or depressed or worried, tense, or anxious, respectively. Overall, 52% of respondents were overweight or obese and 2.5% were underweight. Overweight or obesity were more prevalent among men than women (61.3% vs. 44%) and among American Indians/Alaskan Natives and blacks (59.7%, 63.6%) than among Asians/Pacific Islanders and whites (30.0%, 51.6%). A J-shaped function generally characterized the relationship between BMI and mean number of days depressed or anxious. Underweight and obese respondents reported a greater mean number of days during which they felt depressed or anxious than those with normal BMIs or who were moderately overweight. The association between anxiety and depressive symptoms and obesity was more pronounced among women than men. These findings suggest that among obese individuals, a dose-response relationship exists between BMI and the probability of anxious and depressive symptomatology.

of the serotonergic system is correlated with impulsive aggression. In the current study, we used positron emission tomography (PET) and the radioligands 18F-setoperone and 11C-SCH 23,390 to quantify 5-HT2 and D1 receptor binding, respectively, in eight subjects with MDD with anger attacks and a control population. Data were analyzed using the Simplified Reference Tissue Model, with the cerebellum as the input tissue to solve for the binding potential for 18F-setoperone and 11C-SCH 23,390 in multiple brain regions. Initial analysis did not demonstrate significant global cortical differences in 5-HT2 and D1 binding potential between subjects with MDD with anger attacks and control subjects. Subsequent data of 5-HT2 and D1 binding potential in both populations using circumscribed region of interest analysis of specific brain regions will be presented. Results will be discussed with regard to the role of 5-HT and D1 in the pathophysiology of MDD with anger attacks.

present in humanswith seasonrdaffectivedisorder(SAD)and if their olfactoryperformancecorrelateswithdepressivescores.Becausepreviousstudiessuggesta predominant righthemisphericdysfunctionin SAD and olfactoryneurons’primaryprojectionsare largely ipsilatersf,we tested olfactory identificationperformance on each side of the nose. Twenty-fourSAD patients and twenty-fourmatched controls were studied using bilateraJphenyl ethyl alcohol detectionthresholdsand urrilaterrdUniversityof PennsylvaniaSmellIdentificationTestwithtwo booklets randorrdypresentedto each nostril, the contrafaterrdnostril beingoccluded.Subjectsratedtheirmoodon the SelfAssessmentMood ScaIe for SAD. Patients’ testing was performedin “depressed”and “improvedon light” state. We foundno differencein olfactoryperformancebetweenpatientaandcontrols,norbetweenpatientsbeforevsatler light treatment. A negative correlationemerged between right-sided identification scores and “typical” depression scores (r=–O.56, p=o.006).A similarnegativecorrelationbetwmr the asymmetryindex (Right -Left)/(Right+Left)and typical depressive scores (r=–O.64, p< O.001)was found.These results add to previousevidenceof right hemisphericinvolvementin mood dysregulation.

antidepressanteffectsfor TMS,especiallyleft prefrontalrapidTMS.In normalcontrols,TMS has also been reportedto cause moodchanges specific tObrain side h two separatecontrolledstudies(Georgeet al, 1996;Pascual-Leoneet rd, 1996).Paradoxically,the studiesof normals found increasedsadnesswith left prefrontalstimulationand increased happinesswithrightprefrontalstimulation.ECTis effectivein maniaas well as depression(Smallet al, 1991;Skidaret al, 1994;Black et rd, 1987;Smallet al, 1988).Wethereforeplanneda studyofTMSin mania. Sixteenpatientscompleteda 14daydouble-blindcontrolledtrial of right vs leftprefrontalTMSat 20Hz,2 seconddurationper train,20trainsper day for 10treatmentdays.Maniawas evaluatedusingthe ManiaScale, the Brief PsychiatricRatingScale, and the ClinicalGlobalImpression. Significantlymore improvementwas observedin patientstreated with rightprefrontalTMSthan withleft prefrurrtal.The therapeuticeffect of TMS in mania may show literality oppositeto the effect of TMS in depression.