Change in EEG Activity is Associated with a Decrease in Tinnitus Awareness after rTMS.

OBJECTIVE: To examine how 1Hz and 10Hz rTMS temporarily influence ratings of tinnitus loudness, annoyance, and awareness. The thalamocortical dysrhythmia (TCD) model of tinnitus was tested by examining changes in spectral power and coherence of resting state EEGs from baseline to each phase of treatment and correlating these data with change in tinnitus. METHODS: Nineteen participants completed a double-blind, placebo (sham rTMS) controlled, within-subjects study with crossover between the two active rTMS treatment conditions. An imposed order effect, sham rTMS first, eliminated drift of active treatment into the placebo condition. The primary outcome measures were analogue ratings of tinnitus loudness, annoyance, and awareness, assessed repeatedly at baseline and during treatment, and 64 channel, resting state EEGs collected at baseline and the end of each treatment phase. Active rTMS consisted of 1800 pulses at 110% of motor threshold over temporal cortex delivered at 1Hz and 10Hz over four days. The research design also examined the effect of rTMS immediately following stimulation, regression to the mean in tinnitus ratings made over multiple days, and differences between treatment responders and non-responders. RESULTS: There was no immediate effect of rTMS on tinnitus during a single rTMS session. Regression to the mean in tinnitus ratings occurred over three days of baseline and four days of treatment (both sham and active rTMS). After accounting for regression to the mean in the statistical model, 1Hz rTMS led to a significant decrease in tinnitus awareness from baseline and 10Hz rTMS trended in the same direction, whereas sham rTMS showed little change from baseline other than regression to the mean. Changes from baseline in spectral power of the resting state EEG provided partial support for predictions based on TCD model of tinnitus for active 1 and 10Hz rTMS but not sham rTMS. However, only an increase in beta coherence correlated significantly with a decrease in tinnitus awareness. Changes in the EEG were robust in treatment responders but absent among non-responders and during sham rTMS. CONCLUSIONS: A positive response to rTMS for tinnitus is associated with an rTMS-induced change in beta coherence of the EEG. Increased beta coherence may be a biomarker of the rTMS effect; a "top-down" modulation of the EEG that promotes habituation to tinnitus. Participants whose tinnitus did not improve after rTMS did not show any changes in the EEG.

Lack of adverse cognitive effects of 1 Hz and 20 Hz repetitive transcranial magnetic stimulation at 100% of motor threshold over left prefrontal cortex in depression.

OBJECTIVE: The potential therapeutic effects of repetative transcranial magnetic stimulation (rTMS) are being examined in various neuropsychiatric illnesses. This study assesses the cognitive performance of depressed patients receiving high or low frequency rTMS for 10 days. METHODS: 18 depressed patients participated in a randomized double-blind cross-over study exploring the antidepressant effects of 2 weeks (10 daily) of sham, 1 Hz, or 20 Hz rTMS administered over the left dorsolateral prefrontal cortex at 100% of motor threshold (MT). A subgroup completed a battery of cognitive tests at baseline and following each 2-week phase of treatment, and differences in performance were assessed using paired t -tests and were correlated with the degree of clinical improvement using Hamilton Depression Rating Scale scores. RESULTS: There were no major changes in cognitive test scores as a result of 10 days of either 1 Hz or 20 Hz rTMS. Moreover, any minor attenuations in cognition were not related to the degree of clinical improvement. CONCLUSIONS: Cognitive functioning in many domains following 2 weeks of 1 Hz or 20 Hz rTMS at 100% MT over the left dorsolateral prefrontal cortex in depressed patients is not disrupted.

Post-dexamethasone cortisol correlates with severity of depression before and during carbamazepine treatment in women but not men.

OBJECTIVE: Previous studies show a state-dependent relationship between depression and post-dexamethasone suppression test (DST) cortisol level, as well as differences in DST response with age and gender. METHOD: In this study, 74 research in-patients with affective disorders were given the DST on placebo and in a subgroup following treatment with carbamazepine. Depression was evaluated twice daily with the Bunney-Hamburg (BH) rating scale. Data were examined for the total subject population, by gender and by menopausal status in women. RESULTS: A robust positive correlation was observed between depression severity and post-DST cortisol in pre- and postmenopausal females, but not in males. This relationship persisted in women when restudied on a stable dose of carbamazepine (n=42). CONCLUSION: The pathophysiological implications of this selective positive relationship between severity of depression and post-DST cortisol in women, but not men, should be explored further.

Effects of mood and subtype on cerebral glucose metabolism in treatment-resistant bipolar disorder.

BACKGROUND: Functional brain imaging studies in unipolar and secondary depression have generally found decreased prefrontal cortical activity, but in bipolar disorders findings have been more variable. METHODS: Forty-three medication-free, treatment-resistant, predominantly rapid-cycling bipolar disorder patients and 43 age- and gender-matched healthy control subjects had cerebral glucose metabolism assessed using positron emission tomography and fluorine-18-deoxyglucose. RESULTS: Depressed bipolar disorder patients compared to control subjects had decreased global, absolute prefrontal and anterior paralimbic cortical, and increased normalized subcortical (ventral striatum, thalamus, right amygdala) metabolism. Degree of depression correlated negatively with absolute prefrontal and paralimbic cortical, and positively with normalized anterior paralimbic subcortical metabolism. Increased normalized cerebello-posterior cortical metabolism was seen in all patient subgroups compared to control subjects, independent of mood state, disorder subtype, or cycle frequency. CONCLUSIONS: In bipolar depression, we observed a pattern of prefrontal hypometabolism, consistent with observations in primary unipolar and secondary depression, suggesting this is part of a common neural substrate for depression independent of etiology. In contrast, the cerebello-posterior cortical normalized hypermetabolism seen in all bipolar subgroups (including euthymic) suggests a possible congenital or acquired trait abnormality. The degree to which these findings in treatment-resistant, predominantly rapid-cycling patients pertain to community samples remains to be established.

A placebo-controlled study of lamotrigine and gabapentin monotherapy in refractory mood disorders.

There is a pressing need for additional treatment options for refractory mood disorders. This controlled comparative study evaluated the efficacy of lamotrigine (LTG) and gabapentin (GBP) monotherapy versus placebo (PLC). Thirty-one patients with refractory bipolar and unipolar mood disorders participated in a double-blind, randomized, crossover series of three 6-week monotherapy evaluations including LTG, GBP, and PLC. There was a standardized blinded titration to assess clinical efficacy or to determine the maximum tolerated daily dose (LTG 500 mg or GBP 4,800 mg). The primary outcome measure was the Clinical Global Impressions Scale (CGI) for Bipolar Illness as supplemented by other standard rating instruments. The mean doses at week 6 were 274 +/- 128 mg for LTG and 3,987 +/- 856 mg for GBP. Response rates (CGI ratings of much or very much improved) were the following: LTG, 52% (16/31); GBP, 26% (8/31); and PLC, 23% (7/31) (Cochran's Q = 6.952, df = 2, N = 31, p = 0.031). Post hoc Q differences (df = 1, N = 31) were the following: LTG versus GBP (Qdiff = 5.33, p = 0.011); LTG versus PLC (Qdiff = 4.76, p = 0.022); and GBP versus PLC (Qdiff = 0.08, p = 0.70). With respect to anticonvulsant dose and gender, there was no difference between the responders and the nonresponders. The agents were generally well tolerated. This controlled investigation preliminarily suggests the efficacy of LTG in treatment-refractory affectively ill patients. Further definition of responsive subtypes and the role of these medications in the treatment of mood disorders requires additional study.

Regional cerebral metabolism associated with anxiety symptoms in affective disorder patients.

BACKGROUND: We studied the relationship between regional cerebral metabolism and the severity of anxiety in mood disorder patients, controlling for depression severity. METHODS: Fifty-two medication-free patients with unipolar or bipolar illness underwent positron emission tomography with [(18)F]-fluorodeoxyglucose. Hamilton Depression Rating Scale and Spielberger Anxiety-State Scale scores were obtained for the week of the scan. Analyses were performed on globally normalized images and were corrected for multiple comparisons. RESULTS: After covarying for depression scores, age, and gender, Spielberger Anxiety-State Scale scores correlated directly with regional cerebral metabolism in the right parahippocampal and left anterior cingulate regions, and inversely with metabolism in the cerebellum, left fusiform, left superior temporal, left angular gyrus, and left insula. In contrast, covarying for anxiety scores, age, and gender, Hamilton Depression Rating Scale scores correlated directly with regional cerebral metabolism in the bilateral medial frontal, right anterior cingulate, and right dorsolateral prefrontal cortices. CONCLUSIONS: Comorbid anxiety symptoms are associated with specific cerebral metabolic correlates that partially overlap with those in the primary anxiety disorders and differ from those associated with depression severity.

Cognitive effects of 1- and 20-hertz repetitive transcranial magnetic stimulation in depression: preliminary report.

OBJECTIVE: To determine the cognitive effects of daily repetitive transcranial magnetic stimulation (rTMS) administered under the conditions of a treatment trial for major depression. BACKGROUND: Although daily left dorsal prefrontal rTMS has improved mood in some patients with treatment-refractory depression, potential cognitive side effects of extended daily treatment have not been systematically studied. METHOD: In a randomized double-blind treatment study, 10 subjects (mean age, 42 +/- 15 years) with an episode of major depression received either 2 weeks of low-frequency (1 Hz) or high-frequency (20 Hz) rTMS (800 pulses, 20 trains over 20 minutes, 80% of motor threshold, 5 days per week) to the left dorsolateral prefrontal cortex and then were crossed over to the other treatment condition. Patients received cognitive testing at baseline and after the first and second weeks of low- or high-frequency rTMS, which was examined by repeated-measures ANOVA. RESULTS: Of 16 cognitive measures tested after 1 or 2 weeks of rTMS compared with baseline status, none showed deterioration, and the only significant main treatment effect indicated improvement on a list-recall test from pre- to post-rTMS after 1 week (p <0.05). CONCLUSIONS: These preliminary data suggest no gross deleterious cognitive effects of 2 weeks of 1- or 20-Hz rTMS at 80% of motor threshold over the left prefrontal cortex. Further cognitive studies of the effects of rTMS at other parameters used in clinical trials for mood disorders remain to be undertaken.

Opposite effects of high and low frequency rTMS on regional brain activity in depressed patients.

BACKGROUND: High (10-20 Hz) and low frequency (1-5 Hz) repetitive transcranial magnetic stimulation (rTMS) have been explored for possible therapeutic effects in the treatment of neuropsychiatric disorders. As part of a double-blind, placebo-controlled, crossover study evaluating the antidepressant effect of daily rTMS over the left prefrontal cortex, we evaluated changes in absolute regional cerebral blood flow (rCBF) after treatment with 1- and 20-Hz rTMS. Based on preclinical data, we postulated that high frequency rTMS would increase and low frequency rTMS would decrease flow in frontal and related subcortical circuits. METHODS: Ten medication-free, adult patients with major depression (eight unipolar and two bipolar) were serially imaged using (15)O water and positron emission tomography to measure rCBF. Each patient was scanned at baseline and 72 hours after 10 daily treatments with 20-Hz rTMS and 10 daily treatments with 1 Hz rTMS given in a randomized order. TMS was administered over the left prefrontal cortex at 100% of motor threshold (MT). Significant changes in rCBF from pretreatment baseline were determined by paired t test. RESULTS: Twenty-hertz rTMS over the left prefrontal cortex was associated only with increases in rCBF. Significant increases in rCBF across the group of all 10 patients were located in the prefrontal cortex (L > R), the cingulate gyrus (L >> R), and the left amygdala, as well as bilateral insula, basal ganglia, uncus, hippocampus, parahippocampus, thalamus, and cerebellum. In contrast, 1-Hz rTMS was associated only with decreases in rCBF. Significant decreases in flow were noted in small areas of the right prefrontal cortex, left medial temporal cortex, left basal ganglia, and left amygdala. The changes in mood following the two rTMS frequencies were inversely related (r = -.78, p <.005, n = 10) such that individuals who improved with one frequency worsened with the other. CONCLUSIONS: These data indicate that 2 weeks of daily 20-Hz rTMS over the left prefrontal cortex at 100% MT induce persistent increases in rCBF in bilateral frontal, limbic, and paralimbic regions implicated in depression, whereas 1-Hz rTMS produces more circumscribed decreases (including in the left amygdala). These data demonstrate frequency-dependent, opposite effects of high and low frequency rTMS on local and distant regional brain activity that may have important implications for clinical therapeutics in various neuropsychiatric disorders.

Baseline cerebral hypermetabolism associated with carbamazepine response, and hypometabolism with nimodipine response in mood disorders.

BACKGROUND: Positron emission tomography (PET) studies have reported baseline (medication free) differences between mood disorder patients and healthy control subjects, but relatively little is known about relationships between baseline PET scans and treatment responses. Carbamazepine (CBZ) and to a more limited extent nimodipine (NIMO) seem useful in mood disorders. We explored whether baseline regional cerebral glucose metabolism (rCMRglu) could discriminate CBZ and NIMO responders from nonresponders and healthy control subjects. METHODS: In refractory mood disorder patients, we examined relationships between responses to these drugs, assessed by Clinical Global Impression-Improvement scores, and baseline rCMRglu, determined with fluorine-18 deoxy-glucose and PET. RESULTS: CBZ responders had baseline left insular hyper-metabolism compared to healthy control subjects and nonresponders, whereas nonresponders had widespread (including left insular) hypometabolism. Degree of CBZ response correlated with baseline paralimbic (including insula) and prefrontal hypermetabolism. In responders but not nonresponders, CBZ decreased widespread metabolism, with the degree of decrease in left insula correlating with response. In contrast, NIMO responders but not nonresponders had baseline widespread (including left insular) hypometabolism. Left prefrontal and left insular baseline hypometabolism, but not metabolic changes with treatment correlated with degree of NIMO response. CONCLUSIONS: These data suggest that baseline anterior paralimbic and prefrontal hypermetabolism may be associated with CBZ response, and hypometabolism with NIMO response. Based on these preliminary data, further exploration of relationships between baseline PET scans and treatment responses is indicated.

Regional brain activity during transient self-induced anxiety and anger in healthy adults.

BACKGROUND: Several studies have demonstrated that transient self-induced sadness activates anterior paralimbic structures. To further examine the specificity of these findings and the neural substrates involved in anger and anxiety, we studied the neural correlates of the induction of anxiety and anger in healthy adults. METHODS: We used H2(15)O and positron emission tomography (PET) to measure regional cerebral blood flow (rCBF) in 16 healthy adults during the induction of transient anxiety, anger, and neutral emotions. Subjects achieved differential emotions by recalling prior life events while viewing affect-appropriate faces. RESULTS: Both the anxiety and anger conditions were associated with increased normalized rCBF in left inferior frontal and left temporal pole regions and decreased rCBF in right posterior temporal/parietal and right superior frontal cortex, compared to the neutral induction. Additionally, compared to neutral induction, anxiety was associated with increased rCBF in the left anterior cingulate and cuneus and decreased rCBF in right medial frontal cortex, while the anger induction was uniquely associated with increased rCBF in right temporal pole and thalamus. CONCLUSIONS: Self-generated transient states of anxiety and anger are associated with both overlapping and distinct regional brain activity patterns and provide a template for further dissection of specific components of normal and pathologic emotions.

Lack of correlation between cerebrospinal fluid thyrotropin-releasing hormone (TRH) and TRH-stimulated thyroid-stimulating hormone in patients with depression.

BACKGROUND: It has been proposed that elevated central thyrotropin-releasing hormone (TRH) is associated with the blunted thyroid-stimulating hormone (TSH) response to TRH in patients with depression. Few studies have directly evaluated this relationship between central nervous system and peripheral endocrine systems in the same patient population. METHODS: 15 depressed patients (4 male, 11 female, 12 bipolar, and 3 unipolar) during a double-blind, medication-free period of at least 2 weeks duration, underwent a baseline lumbar puncture followed by a TRH stimulation test. Cerebrospinal fluid (CSF) TRH and serial serum TSH, free thyroxine, triiodothyronine, prolactin, and cortisol were measured. A blunted response to TRH was defined as a delta TSH less than 7 microU/mL. RESULTS: There was no significant difference in mean CSF TRH between "blunters" (2.82 +/- 1.36 pg/mL) and "non-blunters" (3.97 +/- 0.62 pg/mL, p = .40). There was no evidence of an inverse relationship between CSF TRH and baseline or delta TSH. There was no correlation between CSF TRH and the severity of depression or any other endocrine measure. CONCLUSIONS: These data are not consistent with the prediction of hypothalamic TRH hypersecretion and subsequent pituitary down-regulation in depression; however, CSF TRH may be from a nonparaventricular nucleus-hypothalamic source (i.e., limbic area, suprachiasmatic nucleus, brain stem-dorsal raphe) and thus, not necessarily related to peripheral neuroendocrine indices.

Metabolism and excretion of mood stabilizers and new anticonvulsants.

1. The mood stabilizers lithium, carbamazepine (CBZ), and valproate (VPA), have differing pharmacokinetics, structures, mechanisms of action, efficacy spectra, and adverse effects. Lithium has a low therapeutic index and is renally excreted and hence has renally-mediated but not hepatically-mediated drug-drug interactions. 2. CBZ has multiple problematic drug-drug interactions due to its low therapeutic index, metabolism primarily by a single isoform (CYP3A3/4), active epoxide metabolite, susceptibility to CYP3A3/4 or epoxide hydrolase inhibitors, and ability to induce drug metabolism (via both cytochrome P450 oxidation and conjugation). In contrast, VPA has less prominent neurotoxicity and three principal metabolic pathways, rendering it less susceptible to toxicity due to inhibition of its metabolism. However, VPA can increase plasma concentrations of some drugs by inhibiting metabolism and increase free fractions of certain medications by displacing them from plasma proteins. 3. Older anticonvulsants such as phenobarbital and phenytoin induce hepatic metabolism, may produce toxicity due to inhibition of their metabolism, and have not gained general acceptance in the treatment of primary psychiatric disorders. 4. The newer anticonvulsants felbamate, lamotrigine, topiramate, and tiagabine have different hepatically-mediated drug-drug interactions, while the renally excreted gabapentin lacks hepatic drug-drug interactions but may have reduced bioavailability at higher doses. 5. Investigational anticonvulsants such as oxcarbazepine, vigabatrin, and zonisamide appear to have improved pharmacokinetic profiles compared to older agents. 6. Thus, several of the newer anticonvulsants lack the problematic drug-drug interactions seen with older agents, and some may even (based on their mechanisms of action and preliminary preclinical and clinical data) ultimately prove to have novel psychotropic effects.

Repetitive transcranial magnetic stimulation as a neuropsychiatric tool: present status and future potential.

Repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising therapeutic intervention in the treatment of affective disorders. The differences in the type of electrical stimulation required for therapeutic efficacy by rTMS and electroconvulsive therapy (ECT) are discussed. In contrast to ECT, rTMS would not appear to require the generation of a major motor seizure to achieve therapeutic efficacy. Accordingly, it carries the potentially important clinical advantages of not requiring anesthesia and of avoiding side effects such as transient memory loss. Preclinical studies on long-term potentiation (LTP) and long-term depression (LTD) in hippocampal and amygdala slices, as well as clinical data from neuroimaging studies, have provided encouraging clues for potential frequency-dependent effects of rTMS. Preliminary evidence from position emission tomography (PET) scans suggests that higher frequency (20 Hz) stimulation may increase brain glucose metabolism in a transsynaptic fashion, whereas lower frequency (1 Hz) stimulation may decrease it. Therefore, the ability of rTMS to control the frequency as well as the location of stimulation, in addition to its other advantages, has opened up new possibilities for clinical explorations and treatments of neuropsychiatric conditions.

Frequency dependence of antidepressant response to left prefrontal repetitive transcranial magnetic stimulation (rTMS) as a function of baseline cerebral glucose metabolism.

BACKGROUND: Recent studies suggest that both high frequency (10-20 Hz) and low frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) have an antidepressant effect in some individuals. Electrophysiologic data indicate that high frequency rTMS enhances neuronal firing efficacy and that low frequency rTMS has the opposite effect. METHODS: We investigated the antidepressant effects of 10 daily left prefrontal 1 Hz versus 20 Hz rTMS with the hypothesis that within a given subject, antidepressant response would differ by frequency and vary as a function of baseline cerebral glucose metabolism. After baseline PET scans utilizing [18F]-Fluorodeoxyglucose, thirteen subjects participated in a randomized crossover trial of 2 weeks of 20 Hz paired with 2 weeks 1 Hz or placebo rTMS. RESULTS: We found a negative correlation between degree of antidepressant response after 1 Hz compared to 20 Hz rTMS (r = -0.797, p < .004). Additionally, better response to 20 Hz was associated with the degree of baseline hypometabolism, whereas response to 1 Hz rTMS tended to be associated with baseline hypermetabolism. CONCLUSIONS: These preliminary results suggest that antidepressant response to rTMS might vary as a function of stimulation frequency and may depend on pretreatment cerebral metabolism. Further studies combining rTMS and functional neuroimaging are needed.

Gabapentin does not alter single-dose lithium pharmacokinetics.

Lithium (Li) and gabapentin are both exclusively eliminated by renal excretion. When used in combination, a competitive drug-drug interaction could possibly alter Li renal excretion with important clinical implications considering the rather narrow therapeutic index of Li. This study examined the single-dose pharmacokinetic profiles of Li in 13 patients receiving placebo and then steady-state gabapentin (mean daily dose: 3,646.15 mg). During both phases, a single 600-mg dose of Li was orally administered with serial Li levels obtained at time zero and at 0.25, 0.5, 1, 2, 3, 4, 8, 12, 24, 48, and 72 hours. The pharmacokinetic parameters assessed were the following: area under the concentration time curve (AUC) for Li, maximal concentration of Li (Li Cmax), and time to reach peak Li concentration (Li Tmax). For patients receiving gabapentin, the mean Li AUC at 72 hours was 9.91+/-3.54 mmol x hr/mL and did not differ significantly from the mean Li AUC of 10.19+/-2.89 mmol x hr/mL for patients receiving placebo. The mean Li Cmax was 0.69+/-0.13 mmol/L for gabapentin patients and did not differ from the mean Li Cmax of 0.72+/-0.15 mmol/L for placebo patients. The mean serum Li Tmax was 1.38+/-0.62 hours for gabapentin patients and did not differ significantly from the mean serum Li Tmax of 1.5+/-0.91 hours for placebo patients. These data indicate that gabapentin treatment at this high therapeutic dose does not cause clinically significant alterations in short-term Li pharmacokinetics in patients with normal renal function. These preliminary data warrant further controlled study in a larger, more heterogenous patient sample and a longer duration of assessment, but they do suggest that these two medications may be administered in combination for the management of bipolar disorder.

Nimodipine monotherapy and carbamazepine augmentation in patients with refractory recurrent affective illness.

Of 30 patients with treatment-refractory affective illness, 10 showed a moderate to marked response to blind nimodipine monotherapy compared with placebo on the Clinical Global Impressions Scale. Fourteen inadequately responsive patients (3 unipolar [UP], 11 bipolar [BP]) were treated with the blind addition of carbamazepine. Carbamazepine augmentation of nimodipine converted four (29%) of the partial responders to more robust responders. Patients who showed an excellent response to the nimodipine-carbamazepine combination included individual patients with patterns of rapid cycling, ultradian cycling, UP recurrent brief depression, and one with BP type II depression. When verapamil was blindly substituted for nimodipine, two BP patients failed to maintain improvement but responded again to nimodipine and remained well with a blind transition to another dihydropyridine L-type calcium channel blocker (CCB), isradipine. Mechanistic implications of the response to the dihydropyridine L-type CCB nimodipine alone and in combination with carbamazepine are discussed.

The efficacy and use of anticonvulsants in mood disorders.

Carbamazepine and valproate have utility in the acute and prophylactic treatment of mood disorders that appears comparable with that of lithium, but there are emerging differences as well, including responsiveness in some lithium-nonresponsive illness subtypes. Carbamazepine and valproate are generally well tolerated, but each has its own adverse effect profile and proclivity for pharmacokinetic interactions. The high potency (anticonvulsant) benzodiazepines have utility in mood disorders as adjuncts to mood stabilizers and often can obviate the need for neuroleptics. Several small studies suggest that the dihydropyridine L-type calcium channel blockers can be useful mood stabilizers, and several new antiepileptic agents, especially lamotrigine and gabapentin, may have mood-stabilizing properties. The actions of electroconvulsive therapy as they relate to activation of endogenous anticonvulsant processes, and the potential therapeutic effects of nonconvulsive repeated transcranial magnetic stimulation of brain, are promising areas of mood disorder research.

Clozapine in bipolar disorder: treatment implications for other atypical antipsychotics.

Traditional neuroleptics are often utilized clinically for the management of bipolar disorder. Although effective as antimanic agents, their mood stabilizing properties are less clear. Additionally, their acute clinical side effect profile and long term risk of tardive dyskinesia, particularly in mood disorder patients, portend significant liability. This review focuses on the use of atypical antipsychotics in the treatment of bipolar disorder focusing on clozapine as the prototypical agent. Although, preclinical research and clinical experience suggest that the atypical antipsychotics are distinctly different from typical antipsychotics, they themselves are heterogeneous in profiles of neuropharmacology, clinical efficacy, and tolerability. The early clinical experience of clozapine as a potential mood stabilizer suggests greater antimanic than antidepressant properties. Conversely, very preliminary clinical experience with risperidone suggests greater antidepressant than antimanic properties and some liability for triggering or exacerbating mania. Olanzapine and sertindole are under investigation in psychotic mood disorders. The foregoing agents and future drugs with atypical neuroleptic properties should come to play an increasingly important role, compared to the older classical neuroleptics, in the acute and long term management of bipolar disorder.

Beyond lithium in the treatment of bipolar illness.

Dramatic changes have recently occurred in the availability of treatment options for bipolar illness. Second generation mood stabilizing anticonvulsants carbamazepine and valproate are now widely used as alternatives or adjuncts to lithium. High potency benzodiazepines are also used as alternatives to typical neuroleptics, and now atypical neuroleptics are demonstrating efficacy and better side-effects profiles than the typicals. Thyroid augmentation strategies and dihydropyridine L-type calcium channel blockers require further clinical trials to define their role. Putative third generation mood stabilizing anticonvulsants lamotrigine, gabapentin, and topiramate have unique mechanisms of action and deserve further systematic study, as does the potential role for nonconvulsive brain stimulation with repeated transcranial magnetic stimulation (rTMS). These and a host of other potential treatment options now require a new generation of clinical trials to help identify clinical and biological markers of response and optimal use alone and in complex combination therapeutic regimens.