Dimensions of schizophrenia and their time course of response to a second generation antipsychotic olanzapine-A clinical study.

BACKGROUND: The pattern of symptom response to second generation antipsychotics (SGAs) has not been studied extensively. Understanding the time course of symptom response would help to rationally monitor patient progress. OBJECTIVE: To determine the short-term differential time course of response of symptom dimensions of first episode schizophrenia viz., negative, positive symptoms and 5 factors of anergia, thought disturbance, activation, paranoid-belligerence and depression to treatment with SGA olanzapine. METHODS: 57 drug naive patients with schizophrenia were treated for 4 weeks with olanzapine 10mg/day, increased to 20mg/day in 1 week. Weight was recorded and ratings with the Positive and Negative Syndrome scale (PANSS), the Simpson Angus Scale (SAS) were performed weekly. RESULTS: 43 patients completed 4 weeks of assessment. Scores on all of the dimensions improved. By the end of week 1, only positive syndrome, thought disturbance and paranoid-belligerence dimensions improved. Maximum improvement was seen with paranoid-belligerence by week 1, followed by positive syndrome in week 2, and depression at week 3. The percentage improvement in positive syndrome was significantly greater than negative. Over 4 weeks there was a mean weight gain of 2kg and there were significant extrapyramidal symptoms. CONCLUSIONS: Olanzapine produced reduction in all dimensions, but the pace of responding of individual dimensions differed. Longer-term studies comparing SGAs with first generation antipsychotics are needed.

MRI T(2) relaxometry of brain regions and cognitive dysfunction following electroconvulsive therapy.

BACKGROUND: Although electroconvulsive therapy (ECT) causes no structural brain damage, recent studies reported altered brain perfusion acutely following ECT. This is in keeping with brain edema which was noted in animal experiments following electroconvulsive shock. AIM: This study examined alteration in magnetic resonance imaging (MRI) T(2) relaxation time, a measure of brain edema, and its relation to therapeutic efficacy, orientation and memory impairment with ECT. MATERIALS AND METHODS: Fifteen drug-naive consenting patients of major depressive disorder with melancholia (DSM-IV) received ECT as first-line treatment. MRI scans were done before the first ECT and at 2 hours after the second ECT. T(2) relaxation time was measured bilaterally in thalamus, hippocampus, medial temporal lobes and dorsolateral frontal cortex by a blind rater. RESULTS: Depression scores and memory scores were reduced significantly both after the second and fifth ECT. There was no change in T(2) relaxation time after second ECT. CONCLUSION: The finding suggests that ECT does not produce demonstrable change acutely in brain parenchyma detectable by MRI scans.

Cerebellar and other neurological soft signs in antipsychotic-naïve schizophrenia.

OBJECTIVE: Cerebellar neurological abnormalities in schizophrenia have been associated with severe negative symptoms, cognitive deficits, and smaller cerebellar volume. This study assessed the comparative discriminant validity between Cerebellar Soft Signs (CSS) vs. other neurological soft signs (ONSS) [in discriminating between schizophrenia patients and healthy controls] as well as the relationship between the soft signs and psychopathology. METHOD: Antipsychotic-naïve schizophrenia patients (n = 32) and healthy subjects (n = 32) were examined using International Co-Operative Ataxia Rating Scale and Neurological Evaluation Scale. RESULTS: Mean CSS scores, ONSS total score, and Sensory Integration Signs sub-score were significantly higher in patients. Discriminant analysis revealed two CSS sub-scores (but none of the ONSS scores) to be significant (P < 0.0001) accounting for 78% of classification. CSS total score, Posture sub-score, and Oculomotor sub-score had significant positive correlation with negative syndrome score. CONCLUSION: Findings support intrinsic cerebellar dysfunction in schizophrenia. The observations are discussed in relationship with cognitive dysmetria.

Basal ganglia high-energy phosphate metabolism in neuroleptic-naive patients with schizophrenia: a 31-phosphorus magnetic resonance spectroscopic study.

OBJECTIVE: This study used 31-phosphorus magnetic resonance spectroscopy ((31)P MRS) to investigate basal ganglia abnormalities in neuroleptic-naive patients with schizophrenia. METHOD: Nineteen schizophrenia patients and 31 age- and sex-matched healthy comparison subjects underwent (31)P MRS. RESULTS: The phosphocreatine/total phosphorus and phosphocreatine/total ATP ratios in both basal ganglia were significantly lower in patients. CONCLUSIONS: Schizophrenia patients showed features of increased metabolism in the basal ganglia consistent with impaired activity of the frontostriatal pathways.

Effect of ECT stimulus parameters on seizure physiology and outcome.

This study examined the effect of low- and high-pulse frequency stimulus electroconvulsive therapy on seizure physiology and therapeutic outcome. Forty depressed patients randomly received either low (n = 19) or high (n = 21) pulse frequency stimulus during a course of right unilateral electroconvulsive therapy. The current and pulse width were kept constant whereas the duration was proportionately varied. The two groups were compared for seizure parameters and therapeutic outcome. Low frequency stimulus group had lower threshold and less subconvulsive stimulation. There were no differences in seizure durations, ictal cardiovascular responses and therapeutic outcome between the two groups. Low frequency stimulus produced seizure at lower stimulus dose without affecting seizure parameters and therapeutic effects.

Measuring the corpus callosum in schizophrenia: a technique with neuroanatomical and cytoarchtectural basis.

BACKGROUND: Corpus Callosum (CC) abnormalities have been described in schizophrenia. Review of CC measurement methods in schizophrenia reveals inconsistency and lack of neuroanatomical basis. AIMS: The aims of the study are to describe a new CC measurement method with valid a neuroanatomical and cytoarchitectural basis and to demonstrate inter-rater reliability for the same. SETTINGS AND DESIGN: The study was performed in the National Institute of Mental Health & Neurosciences, Bangalore, India. Ours is a cross-sectional study in which both the first author and senior neuroradiologist were blind to clinical details. MATERIAL AND METHODS: We report a reliable, semi-automated CC measuring technique with a neuroanatomical and cytoarchitectural basis tested in a group of 16 never-treated schizophrenia patients using 1-mm thick, objectively defined midsagittal MRI section. Measurement on coded slices using scion image software ensured elimination of rater bias. STATISTICAL ANALYSIS USED: The statistical analysis used for assessing inter-rater reliability is intraclass correlation coefficient analysis. RESULTS: The intraclass correlation coefficients for the CC measurements were as follows: CC Area = 0.93; Anterior CC area = 0.84; Area of body of the CC = 0.83; Area of CC isthmus = 0.65; Area of CC splenium = 0.88; maximum antero-posterior distance of CC = 0.96. CONCLUSION: Measurements showed good inter-rater reliability. The methodology demonstrated in our study is simple, relevant, reliable and can be used for future schizophrenia research.

Seizure threshold in ECT: effect of stimulus pulse frequency.

SUMMARY: Stimulus parameters, such as pulse width, frequency, and stimulus train duration, affect seizure threshold in electroconvulsive therapy (ECT), although variably. This study examined the effect of low- and high-pulse frequencies of stimulus on seizure threshold and physiological responses to ECT. Twenty-four consenting inpatients prescribed ECT by the treating psychiatrist received bilateral ECT. Threshold was reassessed at second and third ECT sessions in a crossover design. In the second ECT the pulse frequency was randomly either 50 pulses per second (PPS; n=13) or 200 PPS (n=11). In the third ECT, the same was reversed. The seizure threshold and number of subconvulsive stimulations were significantly lower with 50 PPS compared with 200 PPS. There was no significant difference in the cardiovascular responses between the two groups. Lower stimulus frequency is more efficient in inducing a seizure (smaller threshold) without compromising the physiological responses to ECT. Clinical effects of different doses of ECT stimulus must also consider the role of charge rate (frequency of pulses).

Neurological soft signs in never-treated schizophrenia.

OBJECTIVE: Studies of Neurological Soft Signs (NSS) in schizophrenia are confounded by handedness, inconsistent methodology, and prior treatment with neuroleptics. The study objective is to examine NSS in never-treated schizophrenia. METHOD: We examined the NSS in treatment-naïve schizophrenia patients (n = 21) and age, sex, education, and handedness matched normal controls (n = 21) using the modified Neurological Evaluation Scale with good inter-rater reliability. RESULTS: Schizophrenia patients had significantly more NSS than normals. No significant correlation was found between illness duration and NSS. CONCLUSION: Higher neurological signs in never-treated patients and their lack of association with illness duration suggest neurodevelopmental etiopathogenesis of schizophrenia.

Reduced Caudate Volume in Never-Treated Schizophrenia : Evidence for Neuro developmental Etiopathogenesis.

BACKGROUND: Evidence suggests that caudate nucleus abnormalities have a role in schizophrenia. Structural brain imaging studies on caudate size in schizophrenia are inconclusive due to confounding factors. METHODS: In this study, caudate volume was measured on coronal Magnetic Resonance Images (I -mm) in consenting 15 never-treated schizophrenia (DSM-IV) patients and 15 age, sex, handedness, education and socioeconomic status matched controls using semi-automated Scion image software. RESULTS: Multivariate analysis revealed significantly smaller caudate volume in patients than controls after controlling for intracranial area (df = 2,27; F = 5.4; p = 0.028). Separate univariate analysis showed that right (df = 2,27; F = 5.4; p = 0.028) and left (df = 2,27; F = 5.2; p = 0.031) caudate were significantly smaller in patients than controls after controlling for intracranial area. Illness duration did not correlate significantly with either right (r = - 0.13; p = 0.65) or left (r = - 0.10; p = 0.7) caudate volume. DISCUSSION: Significantly smaller caudate nucleus in patients with never-treated schizophrenia suggests that some aspect of the disease process of schizophrenia influences the caudate nucleus. In conclusion, smaller caudate volume in never treated schizophrenia with lack of correlation between illness duration and caudate size supports neuro developmental etiopathogenesis in schizophrenia.

Does higher cardiovascular response to ECT predict early antidepressant effect?

BACKGROUND: Effects of diencephalic seizure generalization during ECT, e.g., cardiovascular response, may be relevant in indexing its therapeutic potency. A trend for greater rate pressure product (RPP=heart rate x systolic blood pressure) response to modified ECT in responders than in nonresponders is reported. Atropine used in modified ECT is known to increase RPP. This study examined if cardiovascular response during ECT with or without atropine predicts antidepressant effect. METHODS: Twenty nine consenting, major depressive disorder patients received ECTs. Atropine premedication was randomly withheld in the second or third ECT session. RPP was recorded during ECT. Severity of depression was measured at twice weekly intervals. RESULTS: Fifteen patients remitted at the end of 2 weeks. These early remitters had significantly higher poststimulus RPP than the rest in the ECT session without atropine but not so in the session with atropine. Cumulative poststimulus RPP predicted the early antidepressant response. Corresponding motor or EEG seizure durations were not associated with antidepressant effect. LIMITATIONS: Most patients continued to receive antidepressants. ECT stimulus laterality was not controlled. The study focussed on only short term antidepressant effects. CONCLUSIONS: RPP response to ECT recorded under no-atropine condition may reflect its physiological effects relevant to therapeusis and may have the potential to index seizure adequacy.

Age-at-onset and schizophrenia: reversed gender effect.

OBJECTIVE: This study seeks an explanation for reversed gender effect on age-at-onset (AAO) in schizophrenia. The hypothesis is older AAO in males would be detected in a sample where higher infant mortality (IMR) prevailed. METHOD: Case records of International Classification of Diseases-10 (ICD-10) schizophrenia patients from two states (n=70 each) with an IMR of 13 and 67 per thousand were reviewed and AAO was obtained by using the recorded age and duration of illness. RESULTS: In the sample from the state with lower IMR, AAO did not differ between the two sexes. However, men had older AAO than women in the state with fivefold higher IMR. CONCLUSION: Gender differences in AAO may be a function of perinatal complications. In places where infants with perinatal complications are less likely to survive, hence high IMR, a small group of potentially youngest AAO schizophrenic males may be eliminated thus changing the gender effect on AAO.

Ect in neurological counditions.

It is a myth that electroconvulsive therapy (ECT) produces greater side effects and worsens the neurological condition when used in neurologically ill patients. With the advancement and sophistication in ECT practice standards and modification procedures, it can be safely administered either to treat selected neurological conditions or the co-morbid psychiatric illnesses without additional risks. However ECT should be administered only after thorough evaluation of risks and benefits in such individuals.

Merits of EEG monitoring during ect: a prospective study on 485 patients.

Eliciting cerebral seizure during electroconvulsive therapy (ECT) is essential for therapeutic purposes. When it exceeds beyond 120 seconds (Freeman, 1995) i.e., prolonged, it adds to adverse effects of ECT. Estimating seizure duration using 'cuff method' alone has limitations. This study examined the merits of electroencephalographic (EEG) monitoring in routine ECT practice on a large representative sample. Modified ECT either unilateral or bilateral electrode placement, was administered to 485 patients under EEG monitoring at first ECT session. Ninety one (18.8%) patients had prolonged seizures of which only 59 would have been detected if 'cuff method' alone was used. Twenty nine (6%) patients had inadequate motor seizures but had adequate EEG seizure duration. Twenty five (5.2%) of them had no motor seizure and two such patients even had prolonged seizures. The prolonged seizure was unpredictable in majority. In conclusion, EEG monitoring during ECT is essential to detect both adequacy of cerebral seizure in patients having no or inadequate motor seizures and a/so to detect prolonged seizures.

Ect and t(2) relaxometry: a static walter proton magnetic resonance imaging study.

The aim of the study was to detect brain oedema with electroconvulsive therapy (ECT). Magnetic resonance imaging (MRI) T(2) relaxation time which is an indicator of brain water was measured one day prior to the first ECT and at two hours after second ECT in five depressive patients prescribed right unilateral (RUL) ECT. MRI T(2), relaxation time was measured in hippocampus (He) and thalamus (Th) bilaterally No significant change in T(2) relaxation time following ECT occurred in any of the four regions. EC T did not produce any detectable brain oedema and hence the treatment may be considered safe. The study needs to be replicated in a larger sample and also in bilateral (BL) ECT patient group.

P300 in family studies of schizophrenia: review and critique.

The published studies using P300 event-related potential (ERP) as a vulnerability marker in schizophrenia have been summarized and reviewed. Several factors across sibling, offspring, and familial studies appear to contribute to the variegated findings with respect to the utility of P300 as a vulnerability marker for schizophrenia. These include how subject samples are defined in terms of their genetic loading for schizophrenia, sample size, ERP methodology, and the relationship of P300 measures to neuropsychological test outcomes. It was concluded that the P300 holds promise as a vulnerability marker for schizophrenia, if used in conjunction with other neuroimaging and neuropsychological testing methods.

Seizure threshold estimation by formula method: a prospective study in unilateral ECT.

Formula methods of estimating seizure threshold in bilateral electroconvulsive therapy (ECT) have been successful in 75% (at the first ECT) and 80% (at the sixth ECT) of treatments (Gangadhar et al., 1998). This study showed the same results for unilateral (UL) ECT patients. Its aim was to compare formula and titration methods for threshold determination. The seizure threshold (dependent variable) was determined by the titration method used at the first ECT in consecutive consenting patients (n = 80) prescribed UL ECT under general anesthesia. The independent variables were age, gender, diagnosis, illness severity, concurrent drugs, head circumference, and inion-nasion distance. Forward, step-wise, linear regression analysis showed age as the only significant predictor of seizure threshold (15% of variance). A formula based on regression analysis was prospectively applied in an independent sample (n = 30) of patients receiving UL ECT using the titration method for threshold determination. The results calculated a higher threshold than the actual threshold used in 14 patients, a threshold level in 8 patients, and below threshold in 8 patients. Formula-based estimates would have been successful in 22 (73%) patients, but the majority of them would have received higher than the recommended stimulus dose. Titration is the method preferred for clinical use. However, if a patient's doctor wishes to use the formula-based method, he or she should do so with specific considerations.

Cardiovascular response during ECT: a cross-over study across stimulus conditions.

This study examined the effect of stimulus conditions on rate pressure product (RPP) during ECT. Seizure duration as well as baseline, ictal, and postictal RPP were recorded in 28 patients who received ECT under four stimulus conditions (unilateral threshold, unilateral suprathreshold, bilateral threshold, and bilateral suprathreshold). Seizure duration did not differ between the stimulus conditions. RPP significantly rose from baseline under every stimulus condition. Both ictal and postictal RPP values were different between stimulus conditions (one-way repeated-measure analysis of variance). Pair-wise comparisons showed that unilateral threshold ECT produced significantly lower RPP than unilateral suprathreshold and bilateral suprathreshold ECT conditions. The selective differences in RPP during ECT as well as their correspondence with the known therapeutic potency of ECT under these stimulus conditions suggest that RPP may be a potential index of ECT's therapeutic potency.

Discontinuation of antidepressant drugs during electroconvulsive therapy: a controlled study.

BACKGROUND: The concurrent use of antidepressant drugs with ECT is recommended by a recent ECT guideline. The study aimed to examine differential therapeutic and side effect responses when antidepressants are discontinued or not during ECT. METHODS: This study compared the effectiveness and side effect profile of unilateral ECT with antidepressant drugs (Group-1) or unilateral ECT with drug placebo (Group-2) in 30 major depressive disorder (DSM-IV) patients on antidepressants using a prospective randomised trial. Hamilton Rating Scale for Depression (HRSD), Montgomery Asberg Depression Rating Scale (MADRS), UKU scale, Columbia ECT side effect check list were used. The assessments were carried out before starting ECTs and at fixed intervals thereafter for four weeks. In addition, at six weeks a follow-up assessment was carried out using HRSD. ECTs were stopped after four weeks or earlier if patient obtained HRSD scores <8 and remained so for one week. RESULTS: Continuation of antidepressant drugs with ECT conferred no therapeutic advantage. Barring tricyclic antidepressant induced anticholinergic side effects, no differential side effect profile was noted. At follow-up none relapsed in Group-2 and the mean HRSD scores between the groups did not differ. LIMITATION: The antidepressant treatment prior to ECT was uncontrolled. In addition, the design was not strictly double-blind. CONCLUSION: The study failed to support an advantage with antidepressant continuation during an ECT course in major depressive disorder.

Antidepressant efficacy of Sudarshan Kriya Yoga (SKY) in melancholia: a randomized comparison with electroconvulsive therapy (ECT) and imipramine.

BACKGROUND: Sudarshan Kriya Yoga (SKY) is a procedure that involves essentially rhythmic hyperventilation at different rates of breathing. The antidepressant efficacy of SKY was demonstrated in dysthymia in a prospective, open clinical trial. This study compared the relative antidepressant efficacy of SKY in melancholia with two of the current standard treatments, electroconvulsive therapy (ECT) and imipramine (IMN). METHODS: Consenting, untreated melancholic depressives (n=45) were hospitalized and randomized equally into three treatment groups. They were assessed at recruitment and weekly thereafter for four weeks. RESULTS: Significant reductions in the total scores on Beck Depression Inventory (BDI) and Hamilton Rating Scale for Depression (HRSD) occurred on successive occasions in all three groups. The groups, however, did not differ. Significant interaction between the groups and occasion of assessment occurred. At week three, the SKY group had higher scores than the ECT group but was not different from the IMN group. Remission (total HRSD score of seven or less) rates at the end of the trial were 93, 73 and 67% in the ECT, IMN and SKY groups, respectively. No clinically significant side effects were observed. DISCUSSION: Within the limitations of the design (lack of double blind conditions), it can be concluded that, although inferior to ECT, SKY can be a potential alternative to drugs in melancholia as a first line treatment.