Neuroradiological Aspects of Treatment with Clozapine

Maria B Tome MD MSc, Honorary Registrar;
Michael T Isaac* MA MRCPSYCH, Consultant & Senior Lecturer in Psychiatry
Guy s Hospital, London Bridge, London SE1 9RT England

*to whom correspondence should be addressed



CT scans were carried out on nineteen patients with schizophrenia who did not respond to conventional antipsychotics but who responded to Clozapine, 12 patients with schizophrenia who did not respond either to conventional antipsychotics or to Clozapine, 16 schizophrenics who responded to typical antipsychotics, and 16 normal volunteers. Asymmetry of the anterior horn of the lateral ventricle was associated with lack of response to Clozapine.

Predicting response to antipsychotic drugs has assumed considerable importance with the increasing use of atypical, expensive, and potentially dangerous drugs such as Clozapine. We wished to find out if there were neuroradiological differences between people with schizophrenia who responded to typical antipsychotic drugs, who responded only to atypical antipsychotics, and those who were resistant to all drug treatments, including Clozapine. The availability of a radiological predictor of non-response to Clozapine would clearly be of considerable clinical value. Previous studies (for review, see Nasrallah, 1995) have often been in conflict, with ventricular size being associated with good and bad prognosis.


Patient characteristics

We studied 47 in- and out-patients meeting Research Diagnostic Criteria (RDC: Spitzer et al., 1978) for schizophrenia and 16 normal controls. Thirty-one of the patients received Clozapine. The degree of clinical response was estimated using the Brief Psychiatric Rating Scale (BPRS: Overall and Gorham, 1962). Resistance was defined as more than six months in treatment with a less than 20% decrease in BPRS score (Meltzer, 1989). Nineteen patients responded to Clozapine and 12 proved resistant. All had CT scans as part of their assessment workup. CT scans of patients with schizophrenia, matched for age and sex to the patients receiving Clozapine, and who had responded to conventional antipsychotic drugs (n = 16) were also analysed, together with scans of normal volunteers (n = 16).

CT scans

The scans were generated by a Siemens 9800 CT scanner. Axial scans were performed on slices 1 cm thick parallel to the floor of the anterior fossa and ascending to the vertex. Scans were analysed at an independent viewing console (IVC). Intracranial area was measured on each slice by summing all pixels in the range 0-100 Housefield Units (HU) within the skull. A border just peripheral to the brain cerebrospinal fluid (CSF) boundary of the third ventricle, body, anterior and frontal portion of the lateral ventricle on left and right was traced manually. The IVC was set to summate pixels from 0-25 HU within the area under scrutiny. Bodies of frontal and anterior horns of the lateral ventricular area were measured using the slice that contained the bigger respective area of the lateral ventricles. The area so obtained was divided by the area of the brain similarly obtained on the same slide and multiplied by 100. All measurements were in square centimetres.

Sulcal area was measured, using the most superior slice that still contained lateral ventricular fluid, by tracing manually, within the skull and cerebrum, an annulus that contained the entire cortical outline and sulcal spaces. The IVC summed all pixels between 0 and 25 HU inside this trace to give an estimated area of the sulcal fluid. The boundaries of the interhemispheric fissure (IHF) were traced on the same slice and measured similarly. Right and left Sylvian fissures were defined manually, taking the most superior slice where the anterior horns were visible without the occipital horns or body of the lateral ventricle coming into view. The areas were measured as for the IHF. This methodology is described elsewhere in greater detail (Owen et al, 1988; Jones et al, 1993).

All image analyses were made in ignorance of which group the subjects came from. The areas of the following structures were estimated after the method of Jones et al. (1993), and, in addition, differences between left and right sides were computed, where applicable, for each structure.

Ventricle-to-brain ratios (VBR) were calculated by the measured area in question divided by intracranial area in the same slice following the method of Andreasen et al. (1990).

All measurements were made by the same observer (MBT). Test-retest reliability was ascertained by blind re-measurement of 12 normal controls, with one year between measurements following the procedure of Bland and Altman (1986) and showed <5% difference between measurements.

Statistical analysis

One-way analysis of variance (ANOVA) was used for between-group comparison of continuous variables. A post hoc Scheffe s test was performed in each case. The statistical analyses were performed using SSPS/PC for Windows (v5.0).


Socio-demographic data

The mean age of all subjects was 34.7 years. There were 21 (33.3%) females and 42 (66.6%) males. 56.6% were white European, 26.4% were black (Afro-Caribbean); 9.3% were Asian, and 7.5% were described as of mixed race. Co-variates of sex and age showed no statistical differences between VBR means.

Quantitative measurements

Table of ventricle/brain ratios (mean ? standard deviation) according to diagnostic group. AH, anterior horn of lateral ventricle; CS, cortical sulci; FH, frontal horn of lateral ventricle; L, body of lateral ventricle. The suffix L or R indicates left or right. SA, slice area of 1 CT slice at point of measurement. See text for details of calculations and explanation.
  Responders to Typical Antipsychotics Clozapine Non-Responders Clozapine Responders Normal Subjects Significance*
  11m, 5f;
Mean age 34
6 m; 6f;
Mean age 38
14m 5f;
Mean age 36
11m 5f;
Mean age 31
AHL 0.64 +/-0.16 1.42 +/-0.31 0.71 +/-0.49 0.72 +/-0.28 f=14.45;
AHR 0.61+/- 0.28 0.71 +/-0.18 0.72 +/-0.41 0.66 +/-0.20 ns
CS 0.02 +/-0.07 0.16 +/-0.12 0.39 +/-0.61 0.02 +/-0.10 ns
FHL 0.98 +/-0.41 0.96 +/-0.43 0.92 +/- 0.63 0.83 +/-0.91 ns
FHR 0.90 +/- 0.50 0.86 +/-0.44 0.86 +/-0.33 0.71 +/-0.29 ns
LL 3.42 +/-1.07 2.05 +/-0.54 3.27 +/-1.75 1.98 +/-0.68 f=6.53;
LR 2.97 +/-1.08 1.88 +/-0.71 2.88 +/-1.39 1.91 +/-0.60 f=4.82;
SAL 151.01 +/-9.76 157.45 +/-12.50 158.18 +/-12.52 150.36 +/-10.02 ns
SAFH 158.37 +/-11.60 166.03 +/-13.16 166.71 +/-12.58 157.26 +/-11.42 ns
SAH 157.62 +/-11.15 167.63 +/-14.42 168.24 +/-11.50 160.50 +/-12..70 ns

[*Multiple Range Tests: Scheffe Test with significance level 0.05]

When the left anterior horn VBR means were compared, a statistically significant difference was found between the Clozapine resistant group and the other groups, (f=14.45; p<0.001) which did not differ significantly from one another. No such statistically significant difference could be demonstrated for the right anterior horn. To examine lateral symmetry, the difference between left and right side VBR measurements (i.e., L minus R) was calculated. Here, a statistically significant difference between the Clozapine resistant group and the others was found (f="25.34;" p<0.001). There were no significant differences between measurements of lateral (Sylvian) fissure, interhemispheric fissure and intracranial area among the groups studied.

When the VBR of the bodies of the left lateral ventricles was compared, the mean value for schizophrenic patients who responded to typical antipsychotics was significantly different from the non-responders to Clozapine and the normal subjects; the value for the responders to Clozapine was also significantly different from normal subjects (f=6.53; p<0.0007). When the VBR of the bodies of the right lateral ventricles was compared, only the typical responders and normal subjects showed any significant difference; the other groups showed none (f="4.82;" p<0.0045). Estimation of symmetry of the ventricular bodies was performed as above; no statistically significant differences were discovered.


Our findings indicate that schizophrenic patients who respond either to typical antipsychotics or to Clozapine show increased area of the body of the lateral ventricles, more marked on the left side, compared with control subjects. However, schizophrenic patients who respond to neither typical antipsychotics nor Clozapine are different. These non-responders do not show enlargement of the body of the lateral ventricles, but they show clear enlargement of the left anterior horns. The asymmetries shown up in the present study were not measured in the large-scale study of Jones et al (1993), where, nevertheless, increase in the size of lateral ventricles in people with schizophrenia was demonstrated in comparison with normal controls.

The cause of the cerebral changes may be an important factor in the determination of resistance to treatment. This may be relevant to the subtype of schizophrenia, although our series is too small to make such a hypothesis.

The finding that generalised cerebral atrophy was not associated with failure to respond to Clozapine diverges from the report of Friedman et al (1991), where cerebral atrophy was associated with failure to respond to Clozapine, and was thus cited as a contra-indication to the drug. Patients who after 6 months showed no clinical evidence of improvement and were dropped from the treatment demonstrate statistical differences in mean brain ratios with respect to schizophrenia and Clozapine, but demonstrated no such difference from normal patients. Moreover, our findings suggest further refinement to the argument, most recently put forward by Gerwitz et al. (1994), that the CT scan is an integral part of the management of psychosis, albeit recognising that CT scanning facilities are not universally available.

Treatment options in schizophrenia are relatively few, especially for those who are resistant to treatment with conventional neuroleptics. It may be argued that, given close monitoring, all treatment resistant patients should be considered for a trial of Clozapine. Since such patients have, in some sense, nothing to loose but their symptoms, then this approach may have merit. But itis inescapable that Clozapine is very expensive, and where it does not work, merely increases the cost. Some units in developed countries prescribe very little Clozapine on these grounds alone. It may be that by reproducing and extending studies such as ours, more information that may in the future allow one to predict if Clozapine is likely to be effective, will expand rather than contract its use.


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