Efficacy of ECT in Treatment-Resistant Schizophrenia

The Journal of ECT 2002; 18(2):90-94

Efficacy of Electroconvulsive Therapy Combined with Antipsychotic Medication
in Treatment-Resistant Schizophrenia
Wai Kwong Tang, M.D.; Gabor S. Ungvari, M.D., Ph.D.

Summary:

This study examined the short-term efficacy of electroconvulsive therapy
(ECT) combined with antipsychotic medication in treatment-resistant
schizophrenia (TRS). Fifteen patients with TRS from an in-patient psychiatric
rehabilitation unit participated. Patients completed a course of ECT
consisting of 8 to 20 sessions, while their antipsychotic medications were
continued throughout the study. Patients were assessed at baseline, 1 week, 1
month, and 2 months after their last ECT session. Assessment instruments
included the Brief Psychiatric Rating Scale (BPRS), Hamilton Depression
Rating Scale, Scale for the Assessment of Negative Symptoms (SANS), Global
Assessment Scale (GAS), Clinical Global Impression (CGI), Nurses’ Observation
Scale for In-Patient Evaluation, and occupational therapists’ rating of the
patients’ functioning with respect to work, social, and leisure activities.
Compared with the baseline assessment, at each posttreatment evaluation,
patients showed statistically significant improvement in the GAS and CGI. In
addition, they were significantly better in terms of BPRS and SANS scores, as
well as work performance and social functioning at the 2-month post-ECT
evaluation.

Key Words: Electroconvulsive therapy; Schizophrenia; Clozapine; Treatment
resistance; Electroconvulsive therapy, continuation and maintenance
Department of Psychiatry, Chinese University of Hong Kong, Hong Kong SAR,
China

Accepted June 4, 2002.

Address correspondence and reprint requests to Dr. W. K. Tang, Department of
Psychiatry, 11/F, Prince of Wales Hospital, Shatin, N.T., Hong Kong SAR,
China. E-mail: tangwk@cuhk.edu.hk

The Journal of ECT 2002; 18(2):90-94
Copyright © 2002 Lippincott Williams & Wilkins
All rights reserved

INTRODUCTION

Depending on the definition of antipsychotic treatment resistance, sample
selection, assessment tools, and other methodological aspects of the inquiry,
25-60% of patients with schizophrenia are regarded as treatment resistant (
1, 2). For the purpose of this study, treatment resistance is defined as the
failure to respond to at least two courses of antipsychotic drugs belonging
to different chemical classes, in doses no less than 600 mg chlorpromazine
equivalent given for at least 6 weeks, coupled with a failure to respond to
clozapine in doses of at least 300 mg/d administered for at least 8 weeks, or
refusal to take clozapine. While a number of adjunct treatments for
treatment-resistant schizophrenia (TRS) have been suggested, including
lithium, anticonvulsants, benzodiazepines, and cognitive behavior therapy,
none have proven effective for the majority of patients, a substantial
proportion of whom also fails to show improvement to atypical antipsychotic
drugs ( 3-6).

Patients who are resistant to even repeated trials of atypical antipsychotic
drugs pose a real challenge, as they usually require long periods of
hospitalization, are frequently tormented by positive symptoms, and/or became
extremely withdrawn. Their quality of life is very low by any standard.

Electroconvulsive therapy (ECT), either alone or in combination with
conventional antipsychotic drugs, has been shown to be effective in a certain
percentage of patients with acute schizophrenia ( 7), particularly in the
catatonic subtype and also in schizoaffective disorder ( 8). The use and
efficacy of ECT in chronic schizophrenia is a more controversial topic. Some
authors ( 9) opined that ECT is ineffective in chronic schizophrenia, while
others ( 7) concluded that its efficacy depends on the length of illness and
the frequency and total number of ECT sessions applied.

Lately ECT has come to be regarded as the last resort in patients with
chronic TRS ( 10), although its efficacy has not been systematically
investigated. Anecdotal evidence in the form of case reports ( 11) and case
series ( 12) suggests that ECT combined with conventional antipsychotic drugs
might be effective in TRS. Similarly, ECT combined with clozapine has been
reported effective in several cases of clozapine-resistant schizophrenia
(CRS) ( 13-16). An extensive manual and computer-assisted search including
MEDLINE, EMBASE, and PSYCHINFO databases between 1990 and May 2001 failed to
locate any prospective, open, or controlled study employing a range of
standardized assessment on the use of ECT in TRS in general or CRS in
particular except for one study ( 17) on maintenance ECT in TRS.

We have also noted favorable response to ECT in Chinese patients with acute
episodes of schizophrenia in Hong Kong. According to an unpublished survey
conducted by the principal author, 252 courses of ECT were performed in the
period between July 1997 and July 1998 in our acute psychiatric unit. (A
course is defined as ECT sessions given in consecutive weeks.) Fifty-seven
courses, 23% of all courses of ECT administered during the above-mentioned
period, were administered to patients with schizophrenia or schizoaffective
disorder. The proportion of patients with TRS was unknown. Patients were
given ECT three times a week. The mean number of ECT sessions was 8 (range:
1-21). Based on clinical judgment, varying degree of improvement was noted in
45 (79%) of 57 courses of ECT administered to patients with schizophrenia.

Over the past 3 years, we also have used ECT in combination with traditional
and atypical antipsychotic drugs in a few chronically ill patients with
treatment-resistant schizophrenia (TRS) ( 18). Encouraged by case reports and
our own promising clinical experience, we set out to examine the short-term
therapeutic efficacy of ECT in a prospective study using standardized
assessment in Chinese patients diagnosed with schizophrenia who met criteria
for treatment resistance to traditional antipsychotic drugs ( 19) and either
failed to respond to clozapine and/or other atypical antipsychotic
medications, or refused to take clozapine.

In our clinical practice, ECT-responder TRS patients are offered continuation
and maintenance ECT (ECT-C and ECT-M, respectively) ( 18). In this study, we
also planned to identify those patients who would benefit from ECT-C and
ECT-M.

MATERIALS AND METHODS

Setting and Patients

The study was conducted in a 166-bed psychiatric rehabilitation and extended
care unit in Hong Kong from February 1999 to March 2000. The mean age of the
whole patient population in this facility was 47 ± 14 years, and 67% of them
were male. Prior to the study, all patients who met DSM-IV criteria for
schizophrenia were reassessed for confirmation of their diagnosis and for
criteria of TRS (see below). Patients with the diagnosis of DSM-IV
schizophrenia who fulfilled the criteria of TRS were offered a trial of
clozapine if not previously given. Patients who had proved to be resistant to
clozapine and those who refused clozapine were invited to participate in the
ECT trial. Inclusion criteria were as follows: 1. Age 18-65 years; 2. Both
sexes; 3. Diagnosis of schizophrenia according to DSM-IV criteria; 4. Length
of illness >3 years; 5. At least 6 months of continuous hospitalization; 6.
Resistance to at least two courses of antipsychotic drugs belonging to
different chemical classes, in doses no less than 600 mg chlorpromazine
equivalent, for at least 6 weeks; 7. Refusal to take clozapine or failure to
respond to doses of at least 300 mg/d given for at least 8 weeks; 8. Ability
and willingness to give informed consent. Exclusion criteria were medical
contraindications to ECT and ECT given within the past year.

The Ethics Committee of the Faculty of Medicine, Chinese University of Hong
Kong, granted approval to conduct the study.

ECT Technique

Each patient was given ECT three times a week in a nearby acute psychiatric
unit. A brief-pulse machine (MECTA SR-1; MECTA Corporation, Tualatlin, OR,
U.S.A.) was used. Seizure length was monitored by a one-channel, built-in
electroencephalogram (EEG) and the cuff technique. Thiopentone anesthesia and
succinylcholine were the standard premedications; atropine or glycopyrrolate
was not routinely administered. Only bilateral ECT using bitemporal electrode
placement was given. Seizure threshold was determined in the first ECT
session for every patient by a standard titration protocol ( 9). The total
number of ECT sessions for each patient was determined by the authors’
consensus opinion based on clinical improvement and adverse side effects.
Following earlier studies ( 17, 20-22), we aimed to give a total of 20 ECT
sessions unless adverse effects and/or patient’s refusal shortened the course.

Concurrent Antipsychotic Medication

While waiting for ECT treatment, patients were given olanzapine (=20 mg/day)
or risperidone (=14 mg/day) unless they had failed to respond to these drugs
in the past. These drugs were gradually titrated up to their respective
maximum recommended dose unless adverse side effects prevented an increase.
In keeping with our protocol and rational clinical practice, if patients
responded to these atypical antipsychotic drugs, then ECT would be withheld.
If they did not respond, then a course of ECT would be given. Throughout the
course of ECT, the current antipsychotic drugs were continued at the same
dose. If the patients responded to ECT, the same medication would be
continued after ECT; if ECT was ineffective, patients were offered another
atypical antipsychotic drug.

Psychiatric Assessment

Rating scales to evaluate changes in the patients’ clinical condition
included the Brief Psychiatric Rating Scale (BPRS, 18-item version) ( 23),
Hamilton Depression Rating Scale (HDRS) ( 24), 17-item Chinese language
version, ( 25), Scale for the Assessment of Negative Symptoms (SANS) ( 26),
Global Assessment Scale (GAS) ( 27), Clinical Global Impression (CGI) ( 28),
and the Nurses’ Observation Scale for In-Patient Evaluation (NOSIE-30) ( 29).
The NOSIE-30 was divided into positive (4, 8, 9, 15, 17, 19, and 30) and
negative items (1-3, 5-7, 10-14, 18, and 20-29) as in previous studies ( 30)
and the two groups of items [NOSIE(+) and NOSIE(-)] were entered into the
statistical analysis separately. (For instance, a positive item was #4:
“Shows interest in activities around him” while a negative one was #5: “Sits,
unless directed into activities”.) All ratings were done at baseline and 1,
4, and 8 weeks following the completion of the ECT course.

The principal author, who did not have direct clinical responsibility for the
patients, rated all the clinical scales. Independent from the clinical
ratings, three experienced nurses rated the NOSIE-30. In addition, all
patients were assessed by three occupational therapists 2 months after the
completion of the ECT course or drug treatment with a 5-point scale (from 1 =
very poor to 5 = excellent) on functioning in work (OT-W), social (OT-S), and
leisure (OT-L) activities. No interrater reliability was established for the
ratings made by nurses and occupational therapists.

Statistical Analysis

Descriptive statistics were used to characterize demographic and clinical
data of the study sample. The baseline and posttreatment scores were compared
by repeated measures analysis of variance and within-patient contrast or
Wilcoxon signed ranks test. Statistical significance was set at p < 0.05
level. Ratings of the four patients who were retreated because of a relapse
following an initial response were not separated from the rest of the sample.

RESULTS

One hundred twenty-six patients met DSM-IV criteria for schizophrenia at the
rehabilitation unit, of whom 55 (44%) fulfilled the above criteria for TRS.
Seven patients had ECT in the previous year, thus 48 met the criteria of our
study. Fifteen patients agreed to have ECT, while 24 refused and 9 patients
were unable to comprehend the consent form.

Nine (60%) of the 15 patients consenting to ECT were male. The mean duration
of illness and of lifetime hospitalization was 18.9 ± 5.9 and 9.3 ± 4.5
years, respectively. The mean number of psychiatric admissions was 6.1 ± 4.4.
The mean age of patients and the length of current admission was 40.1 ± 10.5
and 7.2 ± 5.1 years, respectively.

Parameters of ECT

The number of ECT sessions ranged from 8 to 20, with a mean of 15.9 ± 4.2.
ECT was administered three times per week. The mean seizure threshold was
94.9 ± 29.9 mC. The mean maximum stimulus was 318.1 ± 200.7 mC. The mean
seizure duration determined by EEG and the cuff method was 43.0 ± 7.2 and
38.7 ± 5.1 s, respectively.

Past Psychiatric Treatment

Only two patients had received ECT in the past. According to a chart review,
both patients had a good response to past ECT, although the exact magnitude
and length of improvement were not known.

The number of trials with typical antipsychotic medications with a dosage of
at least 600 mg/d chlorpromazine equivalent ranged from 2 to 5. With respect
to atypical antipsychotic drugs, two patients received risperidone, five had
trials of olanzapine and five tried both. Eleven patients were resistant to
clozapine, while clozapine was contraindicated for two patients due to
preexisting neutropenia and atrial flutter; two patients refused to take
clozapine. In the clozapine-resistant group, the maximum dose of drug was 600
mg/d for each patient. The mean length of treatment with maximum clozapine
dose was 11.0 ± 4.2 weeks.

In terms of past adjunct treatment, four patients tried sodium valproate, and
three lithium carbonate. One further patient received both carbamazepine and
sodium valproate.

Antipsychotic Treatment Following ECT

Following the course of ECT, 2 patients were started on olanzapine (10 and 20
mg/day), and 3 received risperidone (2 to 6 mg/day), while 10 continued their
pre-ECT antipsychotic medication.

Psychiatric Assessment

The baseline and post-ECT scores for all rating scales are shown in Table 1.
There were statistically significant differences between the baseline scores
and 1-week, 1-month, and 2-month post-ECT assessment scores of GAS, Clinical
Global Impression (Severity of Illness) [CGI (SOI)], and Clinical Global
Impression (Global Improvement) [CGI (GI)] ratings. In addition, the
difference between baseline and post-2-month scores was also significant for
the BPRS, SANS, OT-W, and OT-L.

TABLE 1. Results of baseline and post-ECT assessment

Judged by the CGI, 6 of the 15 patients did not improve at all, 4 patients
relapsed within 3-6 weeks following initial good treatment response, while 5
patients maintained the improvement for at least 2 months following the last
ECT.

A second course of ECT followed by ECT-C was administered to the four
patients, who, after an initial response, experienced a relapse of symptoms
by 3-6 weeks after the completion of their first ECT course. The number of
ECT sessions in the second course ranged from 6 to 20 for these four patients.

Two of the nine patients who responded to ECT and were offered ECT-C accepted
this treatment option, but only one of them maintained the initial
improvement for 1 year. The second patient’s condition deteriorated within 3
months despite ECT-C.

Adverse Effects of ECT

The only cardiac complication occurred in a previously healthy 41-year-old
male patient who had asymptomatic ST elevation in the V3 and V4 leads of an
electrocardiogram (ECG) following the second ECT session. This ECG
abnormality spontaneously resolved the same day. Cardiological consultation
found no evidence of acute myocardial infarction or any contraindication to
12 further ECT sessions. Postictal confusion was observed in one patient. Two
patients complained of slight, transient memory impairment. Other minor and
transient side effects included headache, dizziness, and pain over the
intravenous site in two patients each.

DISCUSSION

This study targeted the most severely disabled group of schizophrenia
patients whose illness was resistant to most pharmacotherapeutic and social
interventions available. These patients had been confined to hospital for
several years and ECT was the last available treatment of them. There have
been no randomized, controlled studies on the efficacy of ECT in TRS or CRS.
Conducting such studies is very difficult for obvious ethical as well as
logistical reasons. A small-scale open trial ( 31) and case series ( 32, 33)
have shown that ECT could be effective in CRS.

Our study was an open, nonrandomized, prospective trial using standardized
assessment tools. This investigation was designed to measure the short-term
(2-month) outcome of ECT in patients with treatment-resistant chronic
schizophrenia, the majority of whom were also resistant to clozapine,
risperidone, and olanzapine.

The limitations of the study should be acknowledged. The sample size was
relatively small, and no formal cognitive assessment was carried out. In a
pharmacotherapeutic aspect, the study sample was not entirely homogenous, as
not all patients were tried on every available atypical medication prior to
ECT. In addition, the length of clozapine treatment was relatively short, and
its outcome was not measured by standardized rating scales.

The statistical analysis was somewhat confounded by including the ratings for
the four patients who were retreated for a deterioration in their mental
state shortly after their initial good response to ECT. Their 1-month and
2-month post-ECT scores were those following the second course of ECT. This
arrangement is essentially very close to a real clinical situation whereby a
promising, albeit short-lived, improvement to ECT would warrant a further
course of ECT in patients who otherwise were unresponsive to any other
treatment modalities.

Our results indicate that ECT significantly enhanced patients’ global
functioning in the short term. It appears that besides clinical rating
scales, functional assessment should also be included in the outcome measures
when evaluating the usefulness of ECT in TRS or CRS.

ECT significantly reduced positive and negative symptoms, although the
posttreatment BPRS and SANS scores were still very high, indicating
considerable residual psychopathology. While improving the patients’ overall
condition, ECT did not produce a real clinical breakthrough in any patient
even in the short term. However, it did show that there is a potential for
improvement even in patients with chronic schizophrenia unresponsive to most
typical and atypical antipsychotic drugs.

The effect of ECT on affective symptoms was very small, suggesting that the
patients’ improvement was not due to a reduction in affective symptoms.

Without a control group, the possibility of a placebo response in our
patients cannot be excluded, particularly in those four patients who had an
early relapse. However, a robust placebo effect is unlikely, as several
patients maintained initial improvement for more than 2 months. Also, the
majority of staff members voiced strong skepticism towards ECT, thus the
patients could hardly sense the atmosphere of heightened expectations.

Patients who had responded well to ECT gradually deteriorated and returned to
their pre-ECT clinical condition, with the exception of one of two patients
who went on to have ECT-C. (A systematic long-term follow-up is currently
being carried out.) This observation is in accordance with that of other
authors ( 34).

Patients with satisfactory short-term response to ECT are potential
candidates for ECT-C or ECT-M. Recent case reports and case series observed
good results with ECT-M in TRS using an interval of 1 week to 1 month between
ECT sessions ( 17, 35-38). Two of our 15 patients had ECT-C but only one of
them maintained the improvement over 1 year, suggesting that ECT-C and ECT-M
might be useful for selected patients with otherwise intractable TRS.

The optimal number of ECT sessions in patients with schizophrenia remains
controversial. Kendell ( 22) noted that “it used to be widely believed that
schizophrenic patients usually needed between 12 to 20 ECT for maximum
improvement,” but he found no convincing evidence to support this belief.
Fink (personal communication, 1999) also suggested administering up to 20 ECT
sessions in case of clozapine-resistant schizophrenia. In our study, we aimed
to give up to 20 sessions of ECT unless there was a significant improvement
in mental state, or clinically noticeable memory impairment or other adverse
side effects. Seven of our 9 patients who eventually improved with ECT showed
at least some degree of improvement after 12 ECTs; 3 patients’ mental state
further improved when ECT was continued up to a maximum of 20 ECTs. Due to
the paucity of data concerning the number of ECTs in TRS and CRS,
psychiatrists have to rely on their clinical judgment, weighing the benefits
against the adverse effects in each individual patient.

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The Journal of ECT 2002; 18(2):90-94

Comments (2)

dr swapnilAugust 21st, 2008 at 8:47 am

ultimately this study leaves confused opinion for ECT in chronic schizo. more detailed study for chronic relapsing schizo should also be done, who are giving fluctuating response to medicines like clozapine.

chaocoJune 5th, 2010 at 5:23 am

I have schizophrenia and have tried multiple drugs and am mostly allergic to anti psychotics so my response be prerogative. I currently take 1200 lithium, flexiril for neuralgia pain tardive dyskenisia and grimace facial muscle pain, metoprolol tartrate for hypertension due to inflammation or other, and ambien for sleep terror disorder. I have constant auditory and visual hallucinations with two other personalities that try to takeover my main personality for use of my day to day body and I have found that Ambien and other hypnotic sedatives work better than lithium and all other drugs I have taken, I take ten mg ambien and if I stay awake it causes the voices to fall asleep and become much less responsive and much less hallucinatory, though it increases the persistent sexual arousal syndrome they cause as they move around but even this is less in all at its peak. If they could develop a sedative hypnotic i could take during the daytime that does not cause visual hallucinations I would take it and it would be seventy five percent effective rather than the dull twenty five percent effectiveness of lithium and other antipsychotics that do not cause (in some cases) even worse symptoms than the schizophrenia bacteria by itself without any chemical compounds at all.

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