Comparative Study of Clozapine, Electroshock and the Combination of ECT with Clozapine in Treatment-Resistant Schizophrenic Patients
The aim of this study was to compare the results of treatment with clozapine alone, Electroshock (ECT) alone and the combination of clozapine with ECT in treatment-resistant schizophrenic patients. Eighteen treatment-resistant schizophrenic patients were assigned to three equal groups: one group was given clozapine; one group was treated with ECT and one group was treated with the combination of clozapine and ECT. The treatment response was evaluated using the PANSS criteria and the data were analyzed with ANOVA. Combination therapy was superior to single modality therapy. The reduction of PANSS scores was 46% in the clozapine group, 40% in the ECT groups and 71% in the combination group, the difference between the combination group and the other groups was statistically significant (p< 0.05). Patients had a quick response to combination treatment, which resulted in a higher cure rate of positive and negative symptoms and improved the patients general performance. There were no significant adverse effects with combination treatment. Combination treatment with clozapine and ECT was safe and effective in treatment-resistant schizophrenic patients. It should be considered for the treatment of treatment-resistant schizophrenic patients.
With the discovery of antipsychotic drugs in the last 5 decades, particularly
the new generation of drugs in the past few years, many schizophrenic patients
respond well to treatment and can return to their normal lives. However, about
25-30% of schizophrenic patients do not respond to such drug treatment and are
considered to be resistant (Kaplan and Sadock, 2005). Resistant patients are
defined as those who do not respond to two separate groups of antipsychotic
drugs (at a dose equivalent to 20 mg L-1 of haloperidol per day)
after 6 weeks of treatment. In the past few years, clozapine and, in some cases,
ECT were given to such patients, though their effect was not satisfactory. In
contrast to the typical antipsychotic medications that are primarily antagonists
of D2 dopamine receptors, clozapine has little effect on this receptor;
clozapine acts more through the D1, D3 and D4
dopamine and serotonin 5 HT2A receptors (Kaplan and Sadock,
2003). Though the precise mechanism of ECT is not clear, it is thought that
the decline in brain metabolism that occurs after the convulsion has therapeutic
properties. Furthermore, ECT has different effects on various neurotransmitters
that are not yet understood. Clozapine and ECT have different mechanisms and
have both been used in resistant cases, but the results have not been satisfactory.
In recent years, different approaches have been suggested to treat resistant
schizophrenia, including risperidone, clozapine (Chouinard et al., 1994),
olanzapine (Conley et al., 1998; Launer et al., 1997; Ratakonda
et al., 1997; Sheitman et al., 1997), supplemental glycine (Potkin
et al., 1999), famotidine (Oyewumi et al., 1994) and low dose
bromocryptine (Wolf et al., 1992); however, none of them have produced
satisfactory results. Recently, the combination of clozapine and ECT has been
found promising in preliminary studies. Kales and Dequardo (1999) reported the
efficacy of this method in treating 5 schizophrenic patients, Kupchik and Spiva
(2000), studied 36 schizophrenic patients who were resistant to the classic
antipsychotics, clozapine and ECT and found that the combination of clozapine
and ECT was useful in 67% of patients; Kho and Blanstaar (2004) successfully
treated 8 of 11 schizophrenic patients who were resistant to clozapine and other
antipsychotics with a combination of clozapine and ECT. Various case reports
have reported the efficacy of clozapine and ECT used in combination. In fact,
most of the data on the use of the combination of clozapine and ECT have been
from case reports; no comparison studies have been done in which the effects
of combination therapy were compared with the effects of either treatment alone.
Thus, the aim of this study was to determine the safety and effectiveness of
combination therapy in treatment-resistant patients and whether combination
therapy is better than previous therapies.
MATERIALS AND METHODS
In this clinical trial, 18 treatment-resistant schizophrenic patients were
selected from among the patients admitted in Zareh hospital, Sari, Iran, May-Nov.,
2006. The diagnosis of schizophrenia was based on the DSM-IV criteria and was
confirmed by two psychiatrists (the consulting physician and the researcher).
Resistance was defined as lack of response to two separate groups of antipsychotics
given at the proper dose for a sufficient time. Patients with a history of seizures,
clozapine-induced seizures, previous adverse effects on the bone marrow with
clozapine and WBC count below 3500 were excluded from the study. At the beginning
of treatment, a chest X-ray, WBC and EKG were obtained and an anesthesia consultation
was performed. During treatment, weekly CBCs were obtained; cases in which the
WBC count fell below 3500 or was reduced by more than 30% of the previous count
were excluded from the study and referred to a hematologist. All patients gave
their written informed consent prior to beginning treatment. The patients were
matched according to age, gender, type of schizophrenia and symptom severity
(based on the PANSS criteria). The patients were divided into 3 equal groups
of 6 subjects (3 men and 3 women) each. In each group, there were 3 paranoid
schizophrenias, two disorganized and one undifferentiated. One group was treated
with clozapine (after first determining the appropriate dose for 8 weeks); one
group was treated with ECT (12 sessions using the standard unilateral method)
and one group was treated with a combination of ECT and clozapine. In the group
that received clozapine alone, patients were given placebo ECT, consisting of
drug-induced sedation without seizure induction in the ECT room. The group that
received ECT alone was given a clozapine placebo. Prior to treatment, the patients
were drug-free for a 2 week wash-out period. The PANSS test was used to evaluate
the patients symptom severity at the beginning of treatment and then biweekly
to evaluate their response to treatment. Each patient had 5 PANSS tests administered
by a postgraduate psychiatry resident in a double-blind manner. The MMSE test
was also used to assess possible cognitive side effects. The base dose of clozapine
was 200 mg; based on the patients response, the dose was increased as
needed. The minimal number of ECT sessions was 12 (3 times weekly for 4 weeks).
The data were analyzed using SPSS with multi-step measurement or repeated ANOVA.
Each group consisted of 3 men and 3 women. The mean age was 31 years in the clozapine group, 33 years in the ECT group and 31 years in the combined therapy group (Table 1).
The total mean PANSS score at the beginning of treatment was 96 in the clozapine group, 99 in the ECT group and 99 in the combined therapy group; these scores were not significantly different.
The mean positive and negative symptom scores were 23 and 32, respectively for the clozapine group, 31 and 25, respectively, for the ECT group and 33 and 26, respectively, for the combined therapy group; there were no significant differences among the groups. A reduction in the PANSS score reflects response to treatment; a greater reduction in the PANSS score implies a better response to treatment. In the clozapine group, there was a 46% reduction in the mean PANSS score with treatment (before, 96 and after, 52; F = 239.91, Df = 4; 20, p<0.0001). In the ECT group, there was a 40% reduction in the mean PANSS score (before, 99 and after, 60; F = 446.8, df = 4; 20, p< 0.0001). In the combined therapy group, there was 71% reduction in the mean PANSS score (before, 99 and after, 29; F = 1110.1, df = 4; 20, p< 0.00001). The analysis showed that, while all 3 groups had a statistically significant response to treatment, the combination therapy group had a statistically significantly greater response than the other 2 groups (F = 189.15, df = 4, 63, p<0.0001) (Table 2).
|| Patients demographic features by group
|The three groups were matched for age and gender (p<0.05)
||Mean total PANSS scores before and after treatment by treatment
||Mean positive symptoms scores before and after treatment by
|During treatment, the combination therapy group had no severe,
unexpected side effects; the MMSE, test did not reveal any cognitive complications
in any of the patients
Furthermore, the combination therapy group had a statistically significantly
greater reduction in positive symptoms than the other 2 groups (p<0.05).
In the clozapine group, the mean positive symptom score decreased by 31% with
treatment (before, 23 and after, 16; p>0.05); however, the reduction was
not statistically significant. In the ECT group, there was a statistically significant
51% reduction in the mean positive symptoms score with treatment (before, 25
and after, 12; p<0.05). In the combination therapy group, there was a statistically
significant 80% reduction in the mean positive symptom score (before, 26 and
after, 5; p<0.001) (Table 3). With respect to the negative
symptom scores, the clozapine and combination therapy groups had a greater reduction
than the ECT group, though the difference among the groups was not statistically
significant. The mean negative symptom score decreased from 32 to 12 in the
clozapine group (p<0.05), from 33 to 13 in the combination therapy group
(p<0.05) and from 31 to 22 in the ECT group (p>0.05) (Table
The results of this study demonstrate that combination therapy with clozapine
and ECT is more effective than either treatment alone for the treatment of treatment-resistant
schizophrenic patients. Present results are consistent with those reported by
Batia and Gupta (1998), Kales and Dequardo (1999) and Kupchik and Spiva, 2000.
Present study also demonstrated that combination therapy produced a quicker
response, as previously reported by Hames and Gray (1999) and Megged (2001).
In the present study, none of the patients treated with combination ECT and
clozapine therapy experienced serious adverse effects, which is consistent with
the previous report that showed that this combination therapy is not associated
with any complications. Many psychiatrists believe that, in the treatment of
schizophrenia, too much attention is sometimes paid to reduction or elimination
of positive symptoms, while little or no attention is paid to the negative symptoms
or to the various aspects of the patients general performance. Taking this into
account, the number of treatment-resistant schizophrenic patients is actually
much higher than is presently reported. On the other hand, the majority of antipsychotic
drugs (particularly type one) have a greater effect on positive symptoms than
negative symptoms; in fact, some have no effect on the negative symptoms. Two
factors likely account for the synergistic effect seen with the combination
of clozapine and ECT. First, it has been observed that there is a paradoxical
relationship between seizures (abnormal EEG) and psychosis (behavioral and emotional
disorders). In some patients with epilepsy, psychotic symptoms and seizures
occur alternately; when the patient has seizures there are no psychotic symptoms,
but when the seizures are controlled, psychotic symptoms appear despite the
presence of a normal EEG. The term psychosis alternative and forced normalization
is used to describe the probable antagonism between psychosis and seizures or
EEG discharges. On the other hand, the combined use of ECT and clozapine induces
seizure activity and, given the antagonism between psychosis and seizure activity,
this results in the reduction of psychotic symptoms. Another possible explanation
for the mechanism of combined therapy with ECT and clozapine is a change in
the Blood-Brain Barrier (BBB) permeability. An increase in BBB permeability
occurs following a seizure caused by ECT. Kalpan and Sadock (2005) this leads
to the passage of large molecules across blood vessels into the CNS. This allows
a greater amount of clozapine to enter brain tissue without affecting tissue
concentrations in other organs; thus, there is no need to use higher oral doses
of clozapine. The effectiveness of clozapine is dose-dependent (a higher dose
has a more benefit), but higher doses of clozapine are associated with various
side effects. Thus, changes in BBB permeability as a result of ECT allow greater
amounts of clozapine to enter the brain without systemic side effects. In this
way, combination therapy with ECT and clozapine results in a synergistic effect.
This and previous studies have shown that combination therapy with ECT and clozapine
is safe and significantly better than either treatment alone in treatment-resistant
schizophrenic patients. However, a limitation of this study is that the duration
of remission was not studied; future studies will need to address this issue.
On the other hand, treatment stability following ECT termination is not clear.
Kals and Dequardo (1999) emphasized the effectiveness of combination therapy
with ECT and clozapine. Kho and Blansjaar (2004) the effect of studyed of drug-resistant
schizophrenic patients treated with ECT and clozapine and found that patients
had recurrent symptoms after remission; patients were kept in remission with
a maintenance dose of clozapine and weekly ECT. Thus, it could be concluded
that a maintenance dose of clozapine with weekly ECT could result in a short
period of remission. Further follow-up studies of these patients are needed.
Another limitation of this study is the small number of cases. As well, though
a 2-week drug-free wash-out period was used, the long-term carryover effects
of previous drug therapy cannot be completely ruled out. In recent years, combination
therapy involving ECT with clozapine has been used to treat treatment-resistant
type I bipolar disorder patients, particularly those in the manic phase, as
well as for patients with treatment-resistant eating disorders; the preliminary
studies showed promising results (Chanapaltana, 2000). Considering all of these
issues and the results of the present and previous studies, combination therapy
with clozapine and ECT appears to be safe and effective for all of the patients
symptoms, particularly for the negative symptoms and the patients individual,
occupational and social functional disorders. Therefore, it as a suitable alternative
for treatment-resistant schizophrenic patients.
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