Brain effects of TMS delivered over prefrontal cortex in depressed adults: role of stimulation frequency and coil-cortex distance.

Relative regional brain blood flow was measured in 23 clinically depressed adults by using ECD SPECT at baseline and again during actual prefrontal transcranial magnetic stimulation (TMS) following 5 daily sessions of TMS. TMS over prefrontal cortex caused increased activity in cortex directly under the stimulation (inversely correlated with distance from scalp to cortex) and decreased activity in remote regions (anterior cingulate and anterior temporal poles). High-frequency rTMS (20 Hz) caused more relative flow immediately below the TMS coil than did low-frequency rTMS (5 Hz). Confirming the hypotheses tested, repeated daily TMS over the prefrontal cortex in medication-free depressed adults appears to change both local and remote blood flow in a manner that may also depend on the frequency of stimulation and coil to outer cortex distance.

A double-blind placebo-controlled case study of the use of donepezil to improve cognition in a schizoaffective disorder patient: functional MRI correlates.

Cognitive impairment in multiple domains is common in patients with schizophrenia and may be a powerful determinant of poor functional ability and quality of life. We report a double-blind, placebo-controlled, cross-over study of donepezil augmentation in a schizoaffective disorder patient stabilized on olanzapine pharmacotherapy. The patient showed significant improvements in several cognitive measures and increased activation of prefrontal cortex and basal ganglia on functional MRI during the donepezil augmentation. In addition, the donepezil augmentation resulted in a reduction of depressive symptoms and in significant improvements in functional abilities and quality of life. Further studies of donepezil augmentation of neuroleptics in schizophrenia are warranted.

Charleston Antidepressant Drug Interactions Surveillance Program (CADISP).

A prospective antidepressant drug interaction surveillance program was established and collected data for over 4 years in Charleston, SC (Charleston Antidepressant Drug Interactions Surveillance Program, CADISP). One hundred and seventy patients were enrolled. The plasma concentrations and/or clinical effects of drug combinations were monitored in psychiatric patients who received therapy with a selective serotonin reuptake inhibitor (SSRI) or one of the other newer antidepressants (nefazodone, venlafaxine) when combined with other drugs metabolized by the cytochrome P-450 (CYP) enzyme system. Patient data were evaluated to estimate the occurrence and significance of antidepressant-induced metabolic drug interactions. Plasma drug concentrations in the presence and absence of treatment with an antidepressant served as the primary assessment variable. Contrary to the hypothesis that pharmacokinetic drug-drug interactions occur but go undetected, little evidence was found for occultly occurring drug interactions with newer antidepressants. The presence of commonly predicted drug interactions was documented. These data do not eliminate the need for caution when prescribing antidepressants with the potential for causing metabolic interactions, but do help allay the fear that such interactions are highly prevalent and routinely hazardous.

A controlled trial of daily left prefrontal cortex TMS for treating depression.

BACKGROUND: Transcranial magnetic stimulation (TMS) is a new technology for noninvasively stimulating the brain. Several studies have suggested that daily stimulation of the left prefrontal cortex with TMS for 2 weeks has probable antidepressant effects. We conducted a parallel-design, double-masked, sham-controlled study to address whether 2 weeks of daily TMS over the left prefrontal cortex has antidepressant activity greater than sham. METHODS: Thirty medication-free adult outpatients with nonpsychotic, major depressive (n = 21) or bipolar (n = 9) (depressed phase) disorder who were in a current major depression (Hamilton Rating Scale for Depression [HRSD] 21-item score of >18) were treated each weekday for 2 weeks. Subjects were randomly assigned to receive either daily active (20 subjects) or sham (10 subjects) stimulation. Additionally, the 20 active subjects were equally divided between slower (5 Hz) and faster (20 Hz) frequency treatment. Antidepressant response was defined as greater than a 50% improvement in the baseline HRSD. RESULTS: Active TMS resulted in significantly more responders (9/20) than did sham (0/10) (chi(2) = 6.42, p <.01). The number of responders did not differ significantly between the two active cells (3/10 faster and 6/10 slower). Expressed as a percent change from baseline, active TMS subjects had significantly greater improvement on the Beck Depression Inventory as well as the Hamilton Anxiety Rating Scale than did those who received sham. CONCLUSIONS: Daily left prefrontal TMS for 2 weeks significantly reduced depression symptoms greater than did sham. The two forms of active TMS treatment did not differ significantly.

How coil-cortex distance relates to age, motor threshold, and antidepressant response to repetitive transcranial magnetic stimulation.

Repetitive transcranial magnetic stimulation (rTMS) is a tool with antidepressant potential that uses a coil placed on the scalp to produce a powerful magnetic field that directly stimulates only the outermost cortex. MRI scans were obtained in 29 depressed adults involved in an rTMS antidepressant clinical treatment. These scans were analyzed to investigate the effect of distance from coil to cortex on clinical parameters. Longer motor cortex distance, but not prefrontal distance, strongly correlated with increased motor threshold (P<0.01). Clinical antidepressant response did not correlate with either distance. The rTMS antidepressant responders, however, were significantly younger (t=-2.430, P<0.05), and there appears to be a maximum threshold of age and distance to prefrontal cortex for response.

Single-dose pharmacokinetics of methylphenidate in CYP2D6 extensive and poor metabolizers.

Six adults phenotyped as either extensive (N = 4) or poor (N = 2) metabolizers for cytochrome P450 (CYP) 2D6 were given a 10-mg oral dose of methylphenidate (MPH) on two separate occasions with and without quinidine, a potent CYP2D6 inhibitor. Quinidine had no significant effect on the pharmacokinetics of either MPH or ritalinic acid, its major metabolite, in either group of CYP2D6 metabolizers. These data suggest a lack of involvement of CYP2D6 in the metabolism of MPH. Drugs that are inhibitors of CYP2D6 when taken concurrently with MPH should not affect its plasma concentration.

Ethylphenidate formation in human subjects after the administration of a single dose of methylphenidate and ethanol.

Ethylphenidate was recently reported as a novel drug metabolite in two overdose fatalities where there was evidence of methylphenidate and ethanol coingestion. This study explores the pharmacokinetics of ethylphenidate relative to methylphenidate and the major metabolite ritalinic acid, in six healthy subjects who received methylphenidate and ethanol under controlled conditions. Subjects (three males, three females) received a single oral dose of methylphenidate (20 mg; two 10-mg tablets) followed by consumption of ethanol (0.6 g/kg) 30 min later. Methylphenidate, ritalinic acid, and ethylphenidate were quantified using liquid chromatography-tandem mass spectrometry. Ethylphenidate was detectable in the plasma and urine of all subjects after ethanol ingestion. The mean (+/-S.D.) area under the concentration versus time curve for ethylphenidate was 1.2 +/- 0.7 ng/ml/h, representing 2.3 +/- 1.3% that of methylphenidate (48 +/- 12 ng/ml/h). A significant correlation was observed between the area under the concentration versus time curve of methylphenidate and that of ethylphenidate. In view of the known dopaminergic activity of racemic ethylphenidate, it remains possible that under certain circumstances of higher level dosing, e.g., in the abuse of methylphenidate and ethanol, the metabolite ethylphenidate may contribute to drug effects.

Effect of St. John's wort (Hypericum perforatum) on cytochrome P-450 2D6 and 3A4 activity in healthy volunteers.

The effects of the herb St. John's wort (Hypericum perforatum), a purported antidepressant, on the activity of cytochrome P-450 (CYP) 2D6 and 3A4 was assessed in seven normal volunteers. Probe substrates dextromethorphan (2D6 activity) and alprazolam (3A4 activity) were administered orally with and without the co-administration of St. John's wort. Urinary concentrations of dextromethorphan and dextrorphan were quantified and dextromethorphan metabolic ratios (DMRs) determined. Plasma samples were collected (0-60 hrs) for alprazolam pharmacokinetic analysis sufficient to estimate tmax, Cmax, t 1/2, and AUC. Validated HPLC methods were used to quantify all compounds of interest. No statistically significant differences were found in any estimated pharmacokinetic parameter for alprazolam or DMRs. These results suggest that St. John's wort, when taken at recommended doses for depression, is unlikely to inhibit CYP 2D6 or CYP 3A4 activity.

Lack of significant changes on magnetic resonance scans before and after 2 weeks of daily left prefrontal repetitive transcranial magnetic stimulation for depression.

Repetitive transcranial magnetic stimulation (rTMS) is a new technology for exploring brain function. With this method, a small electromagnet is placed on the scalp; by activating and deactivating it, nerve cells in the underlying superficial cortex are depolarized. Several studies have found that prefrontal rTMS has potential efficacy in treating depression, and this technology, in addition to being a research tool, may soon play a role in psychiatric practice. Thus, establishing the safety of this technology is important and has been studied insufficiently. The authors performed T1-weighted three-dimensional volumetric magnetic resonance (MR) imaging on 22 depressed adults (15 active, 7 control) before and after they participated in a 2-week double-blinded, placebo-controlled trial of daily left prefrontal rTMS for the treatment of depression (a total of 16,000 stimuli). Seventeen patients also had paired T2-weighted scans. In a blinded manner, MR scans were qualitatively and quantitatively assessed for structural changes. No qualitative structural differences were observed before and after treatment. In addition, volumetric analysis of the prefrontal lobe showed no changes in the 2 weeks of the study. In conclusion, 10 days of daily prefrontal rTMS at these intensities and frequencies does not cause observable structural changes on MR scans in depressed adults.

Changes in prefrontal cortex and paralimbic activity in depression following two weeks of daily left prefrontal TMS.

Twenty-two depressed adults were scanned with perfusion single-photon computed emission tomography before and after 2 weeks of left perfrontal transcranial magnetic stimulation (TMS) in a parallel design, double-blind treatment study. At medication-free baseline, across all subjects, blood flow in the bilateral medial temporal lobes, left prefrontal cortex, and caudate significantly declined with increased depression severity. Also at baseline, depressed adults who responded to TMS, compared with nonresponders, showed increased inferior frontal lobe activity. Following treatment, there was an even greater difference in inferior frontal blood flow in responders compared with nonresponders, and the negative baseline correlations between depression severity and limbic and prefrontal blood flow disappeared. These results suggest that in depressed adults, 10 days of prefrontal TMS affects prefrontal and paralimbic activity, which may explain its antidepressant effects.

Safety and feasibility of repetitive transcranial magnetic stimulation in the treatment of anxious depression in pregnancy: a case report.

BACKGROUND: The proper treatment of mood disorders occurring during pregnancy is a major therapeutic problem since no antidepressant medications have been established as safe for the developing fetus. Several double-blind placebo-controlled studies have explored the efficacy of repetitive transcranial magnetic stimulation (rTMS) in depression. CASE: We report the case of a 36-year-old woman in her second trimester of pregnancy, whose depression (DSM-IV) and anxiety were successfully treated with rTMS. Further studies of rTMS in depressed pregnant women appear warranted.

Repetitive transcranial magnetic stimulation: perspectives for application in the treatment of bipolar and unipolar disorders.

OBJECTIVES: Transcranial magnetic stimulation (TMS) affects the brain by non-invasively stimulating the cerebral cortex and inducing electrical currents in neurons. The powerful magnetic field acts as a vector that passes across the scalp and the skull, and then converts into an electrical energy within the brain. Originally used in neurophysiology, TMS has since been applied in a variety of neuropsychiatric conditions, including mood disorders. Imaging studies in mood-disordered patients have pointed to dysfunctional limbic and prefrontal cortex activity. TMS researchers have thus postulated that dorsolateral prefrontal cortex (DLPFC) stimulation might change brain activity both locally and in paralimbic areas through transynaptic connections, and alter mood. METHODS: We will describe the technology of TMS, its applications to date, and explore its mechanisms of action. RESULTS: Several clinical trials have demonstrated TMS effects on mood in health and disease. There is a growing consensus that TMS has antidepressant effects, although little is known about the role played by a variety of stimulation parameters such as the intensity or frequency of stimulation. One study has found an antimanic effect of right prefrontal TMS. CONCLUSION: TMS is relatively safe; however, much more research is needed before TMS can be integrated into routine clinical practice.

Extrapyramidal symptoms associated with cyclic antidepressant treatment: a review of the literature and consolidating hypotheses.

Extrapyramidal symptoms (EPS) including parkinsonism, akathisia, dystonia, and tardive dyskinesia have commonly been associated with acute or chronic administration of neuroleptic drugs. A review of the medical literature reveals a substantial number of cases with similar clinical characteristics associated with the tricyclic antidepressants, monoamine oxidase inhibitors, and selective serotonin reuptake inhibitors (SSRIs). Although the data are not sufficient to make definitive pharmacoepidemiologic conclusions, the available number of case reports suggests the SSRIs may be more common offenders in producing these adverse drug effects. The exact mechanism is elusive but likely involves complex interactions of dopamine, serotonin, and norepinephrine between cortical structures and the basal ganglia. The final common pathway for production of EPS seems to be indirect modulation of dopaminergic function. Predictors of patients at risk for antidepressant-induced EPS are not established, but a greater awareness of the potential for these drug side effects to occur may increase their recognition and decrease antidepressant-induced morbidity.

Recent advances in depression research: from stress to molecular biology and brain imaging.

This article will heuristically overview some of the more recent conceptualizations of the pathogenesis and pathophysiology of major depression as well as the functional changes in the central nervous system accompanying its successful pharmacotherapy. The neuropharmacology of affective disorders is a rapidly advancing field of scientific interest with significant complexity and numerous apparently contradictory findings. Within the space limitations of this article, some of the relevant newer conceptualizations of the pathophysiology and treatment of affective disorders will be summarized. Major concepts to be presented include the following: (1) the pathogenesis of affective illness may be conceptualized as an interaction between early and current life stressors and genetic vulnerability; (2) affective illness has been increasingly conceptualized as a potentially chronic progressive illness rather than an intermittent illness with full recovery between episodes; (3) affective illness, including its various stages, may be readily documented and monitored through changes in functional brain imaging; and (4) due to advances in molecular biology technology, there has been increasing evidence documenting changes in genetic activity involved in the pathogenesis of affective disorders from environmental stressors and/or from inherited genetic alterations and of the reversal of these changes accompanying successful pharmacotherapy.

Relation of serum valproate concentration to response in mania.

OBJECTIVE: This study was designed to determine the relation of valproate serum levels to clinical improvement and development of adverse effects in hospitalized patients with acute mania. The initial fixed-dose escalation design, the monotherapy with divalproex, and the control of variables that is possible only with hospitalized patients reduced the confounding factors present in most outpatient studies of serum level-response relationships. METHOD: Sixty-five hospitalized patients who met the Research Diagnostic Criteria for bipolar disorder with mania were treated with divalproex, 750 mg/day for 2 days and then 1,000 mg/day on days 3-5; the dosage was subsequently adjusted as clinically indicated for the remainder of the 21-day study. Manic symptoms were assessed with the Mania Rating Scale, which is derived from the Schedule for Affective Disorders and Schizophrenia. RESULTS: At day 5, patients with serum valproate levels > or = 45 micrograms/ml were two to seven times as likely as patients with levels < 45 micrograms/ml to show 20% or greater improvement in scores on the manic syndrome subscale, the behavior and ideation subscale, elevated mood, increased activity, motor hyperactivity, and psychosis. Endpoint analyses yielded similar results. Adverse experiences characteristic of divalproex treatment were disproportionately associated with serum levels > or = 125 micrograms/ml. CONCLUSIONS: Acutely manic patients treated with divalproex who have valproate serum levels between 45 and 100-125 micrograms/ml are much more likely to have efficacious and well-tolerated responses than patients with lower or higher levels of valproate.

Pathophysiology of schizophrenia and the role of newer antipsychotics.

Schizophrenia is an illness with numerous neurobiologic features. It is hypothesized that patients may have a relative deficit of dopamine neurotransmission in the nigrostriatal and mesocortical tracts of the brain, as contrasted with an excess of dopamine neurotransmission in the mesolimbic area. The dopamine deficit may be related to the negative symptoms (blunted affect, anhedonia, asociality, inability to initiate and carry out complex tasks to completion) of schizophrenia, whereas the dopamine excess may be responsible for the positive symptoms (hallucinations, delusions, and thought disorder). Compared with healthy subjects, schizophrenic patients may also have increased levels of serotonin and decreased levels of norepinephrine in the brain. Conventional antipsychotic drugs nonselectively block dopamine D2 receptors throughout the central nervous system. This may help reduce positive symptoms, but has little or no effect on negative symptoms. Newer agents have more anatomically selective activity with respect to dopaminergic systems but are more complex with respect to their actions in other neurochemical systems, such as serotonin and norepinephrine, which presumably contributes to their apparent greater therapeutic efficacy.

Time course of the corticosteroid-dopaminergic interaction during metyrapone and dexamethasone administration.

Recent studies performed with depressed patients and normal subjects suggest that corticosteroids may alter dopaminergic activity. We measured the time course of the interaction between corticosteroid and plasma homovanillic acid (HVA) levels in 10 young healthy subjects after the administration of 2 mg of dexamethasone in session 1 and after the administration of 4.5 g of metyrapone in session 2. Plasma levels of adrenocorticotropic hormone (ACTH), 11-desoxycortisol, cortisol, HVA, and prolactin (PRL) were measured at 08:00, 09:00, 12:00, 15:00, and 16:00 h on a baseline day and during both drug-administration sessions. Dexamethasone administration resulted in a significant decrease in plasma levels of ACTH, 11-desoxycortisol, and cortisol at all time points and to a significant decrease in PRL secretion in the early morning. Plasma HVA levels were unchanged after dexamethasone administration. Metyrapone administration resulted in a significant decrease in cortisol levels and a significant increase in ACTH and 11-desoxycortisol levels. Plasma HVA levels were significantly increased in the early morning, while PRL levels were unaltered. These results are discussed in relation to the neurochemical and behavioral changes associated with steroid administration and interpreted with regard to a possible association between HVA and PRL in the effects of corticosteroids on dopaminergic activity.

Differences in qualitative brain morphology findings in schizophrenia, major depression, bipolar disorder, and normal volunteers.

This study examined the frequency and type of qualitative brain morphologic anomaly as a function of sex and diagnosis. Magnetic resonance imaging brain scans were evaluated by an experienced neuroradiologist blind to diagnosis. The scans of 325 individuals (108 schizophrenic, 20 schizoaffective, 27 major depressive, 20 bipolar and 150 healthy volunteers) were categorized into one of five groups: normal, hyperintensity signals, volume loss, ventricular anomaly or "other" abnormality. Schizophrenic men had significantly more morphologic anomalies, especially of the lateral ventricles than healthy male volunteers. Schizophrenic women did not differ from healthy women. Schizoaffective patients of both sexes, male depressive and female bipolar patients were also characterized by higher rates of brain anomalies. Independent of diagnosis, women were more likely than men to have hyperintensity signals among individuals with positive scan findings. The overall rate of brain morphologic anomalies is significantly higher among male schizophrenic patients than healthy volunteers; this is not specific to male schizophrenics, however, suggesting a global sex effect. Type of anomaly may differ by sex and give us clues about sex differences in the pathophysiology of psychopathology.