Reward-driven decision-making impairments in schizophrenia.

The ability to use feedback to guide optimal decision-making is essential for goal-directed behaviour. While impairments in feedback-driven decision-making have been associated with schizophrenia and depression, this has been examined primarily in the context of binary probabilistic choice paradigms. In real-world decision-making, however, individuals must make choices when there are more than two competing options that vary in the frequency and magnitude of potential rewards and losses. Thus, the current study examined win-stay/lose-shift (WSLS) behaviour on the Iowa Gambling Task (IGT) in order to evaluate the influence of immediate rewards and losses in guiding real-world decision-making in patients with schizophrenia and major depressive disorder. Fifty-one patients with schizophrenia, 43 patients with major depressive disorder, and 51 healthy controls completed the IGT, as well as a series of clinical and cognitive measures. WSLS was assessed by quantifying trial-by-trial behaviour following rewards and losses on the IGT. Multivariate analyses of variance revealed that patients with schizophrenia demonstrated intact lose-shift behaviour, but significantly reduced win-stay rates compared to healthy controls. In contrast, no WSLS impairments emerged in the depressed group. Win-stay impairments in the schizophrenia group were significantly related to deficits in motivation and cognition. Patients with schizophrenia exhibit impaired reward-driven decision-making in the context of multiple choices with concurrent rewards and losses, and this appears to be driven by a reduced propensity for advantageous win-stay behaviour. With the importance of reward learning and decision-making in generating goal-directed behaviour, these findings suggest a potential mechanism contributing to the motivation deficits seen in schizophrenia.

Investigating consummatory and anticipatory pleasure across motivation deficits in schizophrenia and healthy controls.

Anhedonia has traditionally been considered a characteristic feature of schizophrenia, but the true nature of this deficit remains elusive. This study sought to investigate consummatory and anticipatory pleasure as it relates to motivation deficits. Eighty-four outpatients with schizophrenia and 81 healthy controls were administered the Temporal Experience of Pleasure Scale (TEPS), as well as a battery of clinical and cognitive assessments. Multivariate analyses of variance were used to examine the experience of pleasure as a function of diagnosis, and across levels of motivation deficits (i.e. low vs. moderate. vs. high) in schizophrenia. Hierarchical regression analyses were also conducted to evaluate the predictive value of amotivation in relation to the TEPS. There were no significant differences between schizophrenia and healthy control groups for either consummatory or anticipatory pleasure. Within the schizophrenia patients, only those with high levels of amotivation were significantly impaired in consummatory and anticipatory pleasure compared to low and moderate groups, and compared to healthy controls. Further, our results revealed that amotivation significantly predicts both consummatory and anticipatory pleasure, with no independent contribution of group. Utilizing study samples with a wide range of motivation deficits and incorporating objective paradigms may provide a more comprehensive understanding of hedonic deficits.

Dose-response curve of associative plasticity in human motor cortex and interactions with motor practice.

Associative plasticity is hypothesized to be an important neurophysiological correlate of memory formation and learning with potentials for applications in neurorehabilitation and for the development of new electrophysiological measures to study disorders of cortical plasticity. We hypothesized that the magnitude of the paired associative stimulation (PAS)-induced long-term potentiation (LTP)-like effect depends on the number of pairs in the PAS protocol. We also hypothesized that homeostatic interaction of PAS with subsequent motor learning is related to the magnitude of the PAS-induced LTP-like effect. We studied 10 healthy subjects. In experiment 1a, subjects received 90 (PAS90), 180 (PAS180), or 270 (PAS270) pairs of stimuli, followed by a dynamic motor practice (DMP) 1 h after the end of the PAS protocols. In experiment 1b, the DMP preceded the PAS protocol. In experiment 2, the time course of PAS270 was studied. We found that PAS270 resulted in greater increase in motor evoked potential (MEP) amplitude compared with protocols with fewer pairs of stimuli. Moreover, the interaction between PAS protocols with motor learning differed depending on the number of stimulus pairs used to induce PAS. While DMP alone increased MEP amplitudes, DMP during the LTP-like effects induced by PAS270 led to a long-term depression (LTD)-like effect (homeostatic interaction). This homeostatic interaction did not occur after PAS90 and PAS180. In conclusion, we found a dose-dependent effect of the number of stimulus pairs used in the PAS protocol on cortical plasticity. Homeostatic interaction between PAS and DMP was observed only after PAS270.

Equivalent beneficial effects of unilateral and bilateral prefrontal cortex transcranial magnetic stimulation in a large randomized trial in treatment-resistant major depression.

Repetitive transcranial magnetic stimulation treatment (rTMS) is an effective treatment for depression but the optimal methods of administration have yet to be determined. Recent studies have produced conflicting results as to whether unilateral rTMS is more or less effective than sequentially applied bilateral rTMS. To address this we conducted a trial comparing sequential bilateral rTMS to right-sided unilateral rTMS using a priming protocol. Patients with treatment-resistant depression (n = 179) were enrolled in a two-arm randomized controlled trial across a 4-wk time period. The primary outcome assessment was the Hamilton Depression Rating Scale. Overall, there was a substantial response rate of >50% (and a 40% remission rate); however, there were no significant differences in clinical response between the two treatment groups. rTMS was well tolerated with a very low discontinuation rate. There was no relationship between response in the current trial and previous response, or non-response, to electroconvulsive therapy. We found no significant differences in clinical response between sequential bilateral rTMS and right-sided unilateral rTMS applied with a priming protocol. The results of this study do not support superior efficacy of bilateral rTMS and instead suggest that other approaches should be explored to increase treatment efficacy.

High-frequency repetitive transcranial magnetic stimulation accelerates and enhances the clinical response to antidepressants in major depression: a meta-analysis of randomized, double-blind, and sham-controlled trials.

OBJECTIVE: High-frequency repetitive transcranial magnetic stimulation (HF-rTMS) is a safe and effective treatment for major depression. However, its utility as a strategy to accelerate and improve clinical response to antidepressants is still unclear. DATA SOURCES: We searched the literature from 1995 through May 2012 using EMBASE, PsycINFO, Cochrane Central Register of Controlled Trials, Scopus, and ProQuest Dissertations and Theses, and, from October 2008 until May 2012, by using MEDLINE. We included only studies written in the English language. STUDY SELECTION: We selected all randomized, double-blind, and sham-controlled trials on HF-rTMS used as an accelerating (add-on) strategy to antidepressants for major depression. DATA EXTRACTION: We performed a random effects meta-analysis using odds ratios (ORs) for response and remission rates following HF-rTMS and sham rTMS. Two time points were considered: the end of the add-on HF-rTMS stimulation period (T1) and the end of the study (T2). RESULTS: Data were obtained from 6 randomized controlled trials (RCTs), totaling 392 subjects with major depression. For T1 (at mean ± SD 2.67 ± 0.82 weeks following start of combined rTMS + antidepressant treatment), 6 studies reported on response and 4 on remission rates. We found significantly higher response rates for active HF-rTMS (43.3%; 84/194) compared to sham rTMS (26.8%; 53/198) (OR = 2.5; 95% CI, 1.12-5.56; P = .025); however, remission rates did not differ between groups (P = .33). Heterogeneity between the included RCTs reporting data on response and remission rates at T1 was significant (response: Q5 = 11.4, P = .044, I2 = 56.12; remission: Q3 = 12.24, P = .007, I2 = 75.45). For study end (T2; at mean ± SD 6.80 ± 3.11 weeks following start of combined rTMS + antidepressant treatment), 5 studies reported on response and 4 on remission rates; overall, response rates at T2 were significantly higher for subjects receiving HF-rTMS in comparison to those receiving sham rTMS (62% [104/168] and 46% [79/172], respectively; OR = 1.9; 95% CI, 1.003-3.56; P = .049). Also, 53.8% (57/106) and 38.64% (36/107) of subjects receiving active HF-rTMS and sham rTMS, respectively, were in remission at T2 (OR = 2.42; 95% CI, 1.27-4.61; P = .007). Heterogeneity between the included RCTs reporting data on remission rates at T2 was not significant, although RCTs reporting on response rates at T2 were heterogeneous. The baseline depression scores for active and sham rTMS groups were similar. Finally, HF-rTMS was comparable to sham rTMS in terms of dropout rates. CONCLUSIONS: HF-rTMS is a promising strategy for accelerating clinical response to antidepressants in major depression, providing clinically meaningful benefits that are comparable to those of other agents such as triiodothyronine and pindolol. Furthermore, HF-rTMS seems to be an acceptable treatment for depressed subjects.

New targets for rTMS in depression: a review of convergent evidence.

Although rTMS is moving steadily into the mainstream as a treatment for medically refractory depression, its efficacy continues to lag behind that of more invasive neuromodulation treatments such as ECT or DBS. Here we review evidence to suggest that a fruitful, but neglected, strategy for improving rTMS efficacy may be to explore alternatives to the conventional stimulation target in the dorsolateral prefrontal cortex (DLPFC). The convergent evidence of lesion, stimulation, connectivity, and correlative neuroimaging studies suggests that the DLPFC may have a relatively peripheral role in mood regulation, at least compared to several alternative areas within the prefrontal cortex. In particular, we consider the evidence base in support of four new potential targets for rTMS in depression: dorsomedial prefrontal cortex (DMPFC), frontopolar cortex (FPC), ventromedial prefrontal cortex (VMPFC), and ventrolateral prefrontal cortex (VLPFC). Each of these regions enjoys broader support, from a more diverse evidence base, than the DLPFC in terms of its role in emotion regulation in major depression. We discuss the relative merits of each of these novel targets, including potential obstacles to stimulation using currently available technologies, and potential strategies for overcoming these obstacles. It is hoped that this detailed review will spur a more vigorous exploration of new targets for rTMS in depression. The use of new targets may help to propel rTMS across the threshold of efficacy required of a first-line treatment, to assume a more widespread role in the treatment of depressed mood.

Clinical utility of transcranial direct current stimulation (tDCS) for treating major depression: a systematic review and meta-analysis of randomized, double-blind and sham-controlled trials.

OBJECTIVE: tDCS is a promising novel therapeutic intervention for major depression (MD). However, clinical trials to date have reported conflicting results concerning its efficacy, which likely resulted from low statistical power. Thus, we carried out a systematic review and meta-analysis on randomized, double-blind and controlled trials of tDCS in MD with a focus on clinically relevant outcomes, namely response and remission rates. METHOD: We searched the literature for English language randomized, double-blind and sham-controlled trials (RCTs) on tDCS for treating MD from 1998 through July 2012 using MEDLINE, EMBASE, PsycINFO, Cochrane Central Register of Controlled Trials and SCOPUS. We also consulted the Web of Science's Citations Index Expanded for the selected RCTs up to July 2012. The main outcome measures were response and remission rates. We used a random-effects model and Odds Ratios (OR). RESULTS: Data were obtained from 6 RCTs that included a total of 200 subjects with MD. After an average of 10.8 ± 3.76 tDCS sessions, no significant difference was found between active and sham tDCS in terms of both response (23.3% [24/103] vs. 12.4% [12/97], respectively; OR = 1.97; 95% CI = 0.85-4.57; p = 0.11) and remission (12.2% [12/98] vs. 5.4% [5/92], respectively; OR = 2.13; 95% CI = 0.64-7.06; p = 0.22). Also, no differences between mean baseline depression scores and dropout rates in the active and sham tDCS groups were found. Furthermore, sensitivity analyses excluding RCTs that involved less than 10 treatment sessions or stimulus intensity of less than 2 mA did not alter the findings. However, tDCS used as monotherapy was associated with higher response rates when compared to sham tDCS (p = 0.043). Finally, the risk of publication bias in this meta-analysis was found to be low. CONCLUSIONS: The clinical utility of tDCS as a treatment for MD remains unclear when clinically relevant outcomes such as response and remission rates are considered. Future studies should include larger and more representative samples, investigate how tDCS compares to other therapeutic neuromodulation techniques, as well as identify optimal stimulation parameters.

A double blind randomized trial of unilateral left and bilateral prefrontal cortex transcranial magnetic stimulation in treatment resistant major depression.

OBJECTIVE: A substantive body of research has demonstrated the efficacy of repetitive transcranial magnetic stimulation treatment (rTMS) in patients with depression. However, the parameters needed to optimize therapeutic efficacy remain unclear. The aim of this study was to investigate whether there is an advantage in efficacy of sequential bilateral rTMS compared to standard high-frequency left sided rTMS. METHOD: Sixty seven patients with treatment resistant depression were included in a randomised double-blind sham controlled trial of sequential bilateral rTMS compared to standard high-frequency left sided rTMS and sham rTMS over a three-week period. The study also included a further three week comparison of the two active treatment conditions. The primary outcome variable was scores on the 17-item Hamilton Depression Rating Scale (HAMD). RESULTS: In the three-week double-blind phase of the trial there was a greater antidepressant response to unilateral left sided rTMS compared with sham or bilateral rTMS. Across the full six weeks of active rTMS, there was also a consistent pattern of improved response in unilateral left compared to bilateral treatment. Response rates were low in both active groups. CONCLUSIONS: This study does not support the hypothesis that sequential bilateral rTMS is more effective than unilateral high-frequency left-sided rTMS.

Repetitive transcranial magnetic stimulation for major depressive disorder: a review.

Several studies demonstrated that repetitive transcranial magnetic stimulation (rTMS) is an efficacious treatment for treatment-resistant major depressive disorder (TRD). Recent metaanalyses and more recent large multicentre studies provided evidence suggesting that rTMS is indeed a promising treatment; however, its efficacy has often been shown to be modest, compared with sham stimulation. We review these lines of evidence and discuss several reasons that may explain the modest therapeutic efficacy in most of these studies, including: most involved left-sided treatment alone to the dorsolateral prefrontal cortex (DLPFC) only, which may be less optimal than applying bilateral stimulation; suboptimal methods were used to target the DLPFC (that is, the 5-cm anterior method), limiting the treatment potential of inherently a targeted form of treatment; some treatment durations were short (that is, 2 to 4 weeks); and stimulation intensity might have been insufficient by not considering coil-to-cortex distance, which has been linked to rTMS-induced antidepressant response. Future studies attempting to address the above-mentioned limitations are necessary to potentially optimize the efficacy of this already promising treatment option in TRD. Finally, it is also essential that research investigate the mechanisms of therapeutic efficacy, thus increases in understanding can be translated into enhanced treatment. For several reasons that will be reviewed, cortical excitability may represent an important mechanism, linked to the therapeutic efficacy of this disorder.

A review of repetitive transcranial magnetic stimulation use in the treatment of schizophrenia.

Patients with schizophrenia often fail to respond to standard antipsychotic medications or have a partial treatment response. Few treatment options are available for these patients. Repetitive transcranial magnetic stimulation (rTMS) was developed and investigated over the last 10 years as a potential treatment option for various psychiatric conditions. Increasingly, studies are focusing on potential applications of rTMS in schizophrenia. To date, most of these studies were symptom-specific rather than focused on the treatment of the disorder in general. The most extensive literature focuses on the use of low-frequency stimulation to attempt to disrupt or reduce the intensity of persistent refractory auditory hallucinations. This research tends to suggest that rTMS could have a role in this subset of patients. There is also preliminary but limited evidence that rTMS could have a role in reducing the negative symptoms of schizophrenia and perhaps in augmenting cognitive function. These findings also highlight the pressing need for further research including multisite studies to confirm the value of these options.

Hippocampal volumetrics in depression: the importance of the posterior tail.

Studies of patients with major depression disorder (MDD) have revealed reduced hippocampal volumes, but findings have been inconsistent due to sample and measurement differences. The current study sought to measure this structure in a large sample of MDD and control subjects, using a strict measurement protocol, in order to elucidate morphological-specific volumetric differences. Forty-five subjects with treatment-resistant MDD and 26 controls underwent psychiatric assessments and brain magnetic resonance imaging (MRI). The findings of this study indicate that (1) MDD results in reduced hippocampal volume, particularly in the tail section, (2) region of interest (ROI) estimation protocols and sample characteristics may help explain volumetric differences between previous MDD studies, and (3) specific ROI atrophy in treatment-resistant depression is influenced by sex.

A preliminary fMRI study of the effects on cortical activation of the treatment of refractory auditory hallucinations with rTMS.

Three patients underwent fMRI during a word generation task before and after successful treatment of auditory hallucinations with rTMS and were compared to four control subjects. There was a significant increase and more normal task related brain activation in brain areas involved in language processing including left temporoparietal cortex after rTMS treatment.

A randomized trial of low-frequency right-prefrontal-cortex transcranial magnetic stimulation as augmentation in treatment-resistant major depression.

Low-frequency right prefrontal repetitive transcranial magnetic stimulation (rTMS) appears to have antidepressant properties although the effectiveness of this treatment in clinical practice has not been assessed nor have the optimal stimulation parameters been adequately defined. A total of 130 patients with treatment-resistant depression were randomized to either 1- or 2-Hz rTMS over the right prefrontal cortex (PFC) for 2 wk with a possible further 2 wk extension. Non-responders were randomized to either 5- or 10-Hz left PFC rTMS. Overall, 66 patients (51%) achieved response and 35 (27%) remission criteria. For right-sided treatment, depression significantly improved but there was no between-group difference. Twenty-eight (42%) patients in the 1-Hz group and 33 (53%) patients in the 2-Hz group achieved response criteria (chi2=1.40, p>0.05). Depression symptom scores also improved for patients who crossed over to left-sided treatment but there was no significant difference in response between 5- and 10-Hz rTMS. Despite a heterogeneous sample, a significant proportion of patients met clinical response criteria following treatment but response to 1 and 2 Hz did not differ. 2-Hz right PFC rTMS has antidepressant properties but offers no advantage over 1 Hz despite doubling pulse number.

Naturalistic study of the use of transcranial magnetic stimulation in the treatment of depressive relapse.

BACKGROUND: The efficacy of repetitive transcranial magnetic stimulation (rTMS) in the treatment of depression has been assessed in a number of acute treatment trials during the last 10 years. Little is known about the long-term impact of the treatment on the disorder and its effectiveness when applied for repeated relapses of depression over time. METHOD: Nineteen patients who had previously responded to rTMS in clinical trials received treatment with rTMS for a total of 30 episodes of depressive relapse. RESULTS: Approximately 10 months elapsed between treatment episodes. The majority of patients achieved a significant improvement in each treatment course with significant improvements achieved in patients treated with both low-frequency right-sided rTMS and high-frequency left-sided rTMS. CONCLUSIONS: The study suggests that rTMS may have value in the treatment of episodes of depressive relapse with little reduction in efficacy over time.

A randomized, controlled trial of sequential bilateral repetitive transcranial magnetic stimulation for treatment-resistant depression.

OBJECTIVE: High-frequency left-side repetitive transcranial magnetic stimulation (rTMS) and low-frequency stimulation to the right prefrontal cortex have both been shown to have antidepressant effects, but doubts remain about the magnitude of previously demonstrated treatment effects. The authors evaluated sequentially combined high-frequency left-side rTMS and low-frequency rTMS to the right prefrontal cortex for treatment-resistant depression. METHOD: The authors conducted a 6-week double-blind, randomized, sham-controlled trial in 50 patients with treatment-resistant depression. Three trains of low-frequency rTMS to the right prefrontal cortex of 140 seconds' duration at 1 Hz were applied daily, followed immediately by 15 trains of 5 seconds' duration of high-frequency left-side rTMS at 10 Hz. Sham stimulation was applied with the coil angled at 45 degrees from the scalp, resting on the side of one wing of the coil. The primary outcome variable was the score on the Montgomery-Asberg Depression Rating Scale. RESULTS: There was a significantly greater response to active than sham stimulation at 2 weeks and across the full duration of the study. A significant proportion of the study group receiving active treatment met response (11 of 25 [44%]) or remission (nine of 25 [36%]) criteria by study end compared to the sham stimulation group (two of 25 [8%] and none of 25 respectively). CONCLUSIONS: Sequentially applying both high-frequency left-side rTMS and low-frequency rTMS to the right prefrontal cortex, has substantial treatment efficacy in patients with treatment-resistant major depression. The treatment response accumulates to a clinically meaningful level over 4 to 6 weeks of active treatment.

Repetitive transcranial magnetic stimulation reveals abnormal plastic response to premotor cortex stimulation in schizophrenia.

BACKGROUND: Schizophrenia may be characterized by abnormal plastic modulation in cortical neuronal circuits. Activation of premotor cortex using repetitive transcranial magnetic stimulation (rTMS) produces suppression of cortical excitability in primary motor cortex. We hypothesized that premotor rTMS would cause less suppression of motor cortical excitability in patients with schizophrenia than in control subjects. METHODS: Twelve patients diagnosed with schizophrenia and twelve healthy control subjects underwent subthreshold rTMS to the premotor area in a 15-min conditioning train. Measurements of primary motor cortical excitability (motor evoked potential; MEP), the resting motor threshold (RMT), and cortical inhibition (CI) were taken before and after the rTMS. RESULTS: There was no difference in RMT between groups at baseline, although the patient group had less CI than the control group at baseline. Following rTMS, the change in both MEP size and RMT between groups was significant. After rTMS, MEP size was suppressed in the control group and increased in the patient group, whereas RMT increased in the normal control group and decreased in the patient group. CONCLUSIONS: Patients with schizophrenia demonstrate abnormal brain responses to rTMS applied to the premotor cortex that appear to relate to reduced motor cortical inhibition.

Motor cortical excitability and clinical response to rTMS in depression.

BACKGROUND: The relationship between frontal lobe activity in the left and right hemispheres and the pathophysiology of depression remains unclear. In addition, it is uncertain whether levels of frontal or motor cortical excitability relate to clinical response to treatment modalities. We aimed to explore whether motor cortical excitability as assessed with single and paired pulse transcranial magnetic stimulation (TMS) could be used to predict the response to treatment with repetitive TMS (rTMS) applied to the left or right prefrontal cortex. METHODS: Motor thresholds, cortical excitability and cortical inhibition (CI) were assessed prior to a trial of rTMS in patients with treatment resistant depression. RESULTS: There was no consistent pattern of differences in hemispheric activity, although there was a relationship between the degree of psychopathology and cortical excitability (right hemisphere) and an inverse relationship between inhibitory activity and clinical response (left hemisphere). CONCLUSIONS: The study does not support a simple model of laterality in motor cortical excitability in depression. The TMS measures used in this study appear to be of limited use in the prediction of clinical response to rTMS.

Reduced plastic brain responses in schizophrenia: a transcranial magnetic stimulation study.

BACKGROUND: Abnormalities in brain plasticity, possibly related to abnormal cortical inhibition (CI), have been proposed to underlie the pathophysiology of schizophrenia. Transcranial magnetic stimulation (TMS) provides a dynamic method for non-invasive study of plastic processes in the human brain. We aimed to determine whether patients with schizophrenia would exhibit an abnormal response to repetitive TMS (rTMS) applied to the motor cortex and whether this would relate to deficient cortical inhibition. METHODS: Measures of motor cortical excitability and cortical inhibition were made before and after a single 15-min train of 1-Hz rTMS applied to the motor cortex in medicated and unmedicated patients with schizophrenia as well as healthy controls. RESULTS: All three groups had equal motor cortical excitability prior to rTMS, although both patient groups had a shorter cortical silent period (CSP) and less cortical inhibition than the control group. Cortical excitability, as assessed by motor threshold levels, did not reduce in both medicated and unmedicated patients in response to rTMS as was seen in the control group. Significant differences were also seen between the groups in response to the rTMS for motor-evoked potential (MEP) size and cortical silent period duration. CONCLUSIONS: Both medicated and medication free patients with schizophrenia demonstrated reduced brain responses to rTMS and deficits in cortical inhibition.

Transcranial magnetic stimulation in the treatment of depression: a double-blind, placebo-controlled trial.

BACKGROUND: High-frequency left-sided repetitive transcranial magnetic stimulation (HFL-TMS) has been shown to have antidepressant effects in double-blind trials. Low-frequency stimulation to the right prefrontal cortex (LFR-TMS) has also shown promise, although it has not been assessed in treatment-resistant depression and its effects have not been compared with those of HFL-TMS. OBJECTIVE: To prospectively evaluate the efficacy of HFL-TMS and LFR-TMS in treatment-resistant depression and compared with a sham-treated control group. DESIGN: A double-blind, randomized, sham-controlled trial. SETTING: Two general psychiatric services. PARTICIPANTS: Sixty patients with treatment-resistant depression who had failed to respond to therapy with multiple antidepressant medications were divided into 3 groups of 20 that did not differ in age, sex, or any clinical variables. All patients completed the double-blind phase of the study. INTERVENTIONS: Twenty 5-second HFL-TMS trains at 10 Hz and five 60-second LFR-TMS trains at 1 Hz were applied daily. Sham stimulation was applied with the coil angled at 45 degrees from the scalp, resting on the side of one wing of the coil. Main Outcome Measure Score on the Montgomery-Asberg Depression Rating Scale. RESULTS: There was a significant difference in response among the 3 groups (F56,2 = 6.2), with a significant difference between the HFL-TMS and sham groups and between the LFR-TMS and sham groups (P<.005 for all) but not between the 2 treatment groups. Baseline psychomotor agitation predicted successful response to treatment. CONCLUSIONS: Both HFL-TMS and LFR-TMS have treatment efficacy in patients with medication-resistant major depression. Treatment for at least 4 weeks is necessary for clinically meaningful benefits to be achieved. Treatment with LFR-TMS may prove to be an appropriate initial repetitive TMS strategy in depression taking into account safety, tolerability, and efficacy considerations.

Actigraphic measurement of the effects of single-dose haloperidol and olanzapine on spontaneous motor activity in normal subjects.

OBJECTIVE: To quantitatively examine the effects of haloperidol and olanzapine on spontaneous motor activity in normal subjects. DESIGN: Randomized, double-blind, placebo-controlled medication study. PARTICIPANTS: Normal volunteers (n = 30). INTERVENTIONS: Subjects received 1 dose of either haloperidol 2 mg (n = 9), olanzapine 10 mg (n = 10) or placebo (n = 10) and were admitted to hospital for the next 24 hours. OUTCOME MEASURES: Subjects wore an actigraphic monitor, which recorded movement in 15-second epochs. The Simpson-Angus Extrapyramidal Side Effect Scale (SAS) and the Barnes Akathisia Scale (BAS) were administered before and 7 and 24 hours after medication was given. RESULTS: Compared with placebo, total motor activity was decreased by 41% with olanzapine (p = 0.004) and by 12% with haloperidol (NS). There were significantly more epochs with zero movement with olanzapine than with haloperidol or placebo. For non-zero epochs, the mean activity count and the distribution of activity counts did not differ significantly among groups. There were no positive findings on the SAS or the BAS. CONCLUSIONS: Olanzapine decreased total motor activity by increasing the amount of time during which subjects were immobile, rather than by affecting the magnitude of movement during periods in which there was activity. This effect occurred at a dose of olanzapine low enough not to cause clinically observed extrapyramidal side effects. Our results suggest that actigraphy is useful as a sensitive, noninvasive tool for measuring the effect of antipsychotics on spontaneous motor activity.