Marked Hypofrontality in Clozapine-responsive Patients

• Abstract
• Introduction
• Patients and Methods
• PET procedure
• Image analysis
• Statistics
• Clinical data
• Metabolic data
• Results
• Activity differences between TR-clozapine treated patients and controls
• Activity differentes between TR-clozapine treated and NN patients
• Discussion
• Acknowledgements
• References

Abstract

Previous data show that the effects of clozapine on regional brain activity are different from those of other antipsychotic agents. It seemed of interest to study the brain activity patterns after treatment with clozapine, since this drug might correct basal deficits directly related to schizophrenia or instead induce changes that would in some way compensate distant abnormalities. In order to study the activity pattern resulting from clozapine treatment we have used FDG-PET and statistical parametric mapping (SPM) to explore the functional status of patients after chronic treatment with this drug, We compared their metabolic activity with normal controls and neuroleptic-naive (NN) patients, with the aim to identify if a reversion of pre-existing deficits or a induction of different changes was the result of clozapine administration. We compared metabolic patterns in 23 treatment-resistant (TR) patients after 6 months of treatment with clozapine, eighteen healthy subjects, and 17 NN schizophrenia patients. After treatment with clozapine, TR patients showed a clear hypofrontality and caudate hypometabolism in comparison with both the controls and NN patients, and also a lower thalamic activity than the healthy controls. In conclusion, our results support a preferential role for prefrontal regions and their subcortical connections in the mechanism of action of clozapine, resulting in a clearly hypofrontal state as compared to both controls and schizophrenia patients without previous treatment.

Introduction

Hypofrontality during cognitive tasks is a consistent finding in schizophrenia [2] [5]. Such hypofrontality is present in neuroleptic-naïve patients, even before a diagnosis of schizophrenia can be made [30].

Despite this, treatment with antipsychotics may also contribute to hypofrontality. Typical antipsychotics may induce a decrease in frontal activity [17], but the decrease in frontal activity may be even greater with clozapine, even in cases with a good clinical outcome [6] [19] [28]. Data using single photon emission tomography support a greater perfusion decrease in repsonders to clozapine [35], which is otherwise coherent with the EEG slowing reported to be associated with clozapine response [15].

Since clozapine is one of the most effective antipsychotics, the stronger decrease in frontal activity observed after administration of this drug is intriguing. Because it is unlikely that decreases in frontal activity would be therapeutic per se, clozapine could exert a compensatory action on other areas by decreases in such activity rather than correcting basal deficits in the frontal region. This idea would be of interest, given the evidence supporting a deficit of the inhibitory function in cortical regions in schizophrenia [38] [39], that could be particularly compensated by clozapine, as suggested by preclinical data [43].

With a view to studying hypofrontality as a result of treatment with clozapine, here we re-analyzed the data from patients included in a previous study in which pre- and post-clozapine metabolic rates were compared directly [28]. In that study we found a decrease in frontal activity at rest after six months on clozapine as compared to a chronic treatment with haloperidol. In the present work, we compared the post-clozapine data with those obtained in a normal group and a group of schizophrenia patients without previous treatment. Our hypothesis was that a hypofrontal state would be a direct effect of clozapine.

Patients and Methods

Using statistical parametric mapping (SPM), we compared the metabolic data obtained with fluorodeoxyglucose positron emission tomography (FDG-PET) in 23 treatment-resistant (TR) patients (16 males) after six months on clozapine with respect to those found in 17 neuroleptic-naive (NN) patients (14 males) and 18 healthy controls (13 males). TR patients had evidenced a poor response [at least a psychotic symptom scoring equal or higher than 4 in the SAPS and a clinical global impression (CGI) of 4 or more] to at least two different classical treatments during the previous year, each one lasting for more than one month, at doses above 800 mg/d in CPZ equivalents.

Thirty-four TR patients had been initially included, but 11 of them were lost during follow-up, thus only the 23 here included completed the follow-up. We used CGI scores to rate improvement from baseline to the end of follow-up (6 months later). The patients were recruited as consecutive admissions to a psychiatric ward in a general hospital, and then were followed in the community mental health services by one of the investigators (VM or JS)

The PET studies were performed under resting conditions. The clinical and demographic of the subjects included in the study data are presented in [Table 1].

The follow-up PET scan was made after 6 months of treatment with clozapine in the TR group, titrated up to an effective dose to each patient (on clinical grounds). The minimum and maximum doses were respectively 300 mg/d and 600 mg/d. The mean final clozapine dose was 477.56 mg/d (SD: 109.25). Once the effective dose was reached, to the judgment of the treating clinician, that dose was kept stable to the end of follow-up, except in case of intolerance. The patients received no other medication than clozapine. Compliance with clozapine treatment was monitored by weekly interviews during the study period, taking into account a clinical examination (psychiatric status and side effects) and the information collected from the patients and their relatives. In all cases, according to the same sources of information compliance was deemed to have been good during this period. Serum clozapine levels were not available to us by the time of PET scans. Blood cell counts were performed according to the protocol for clozapine prescription in Spain (weekly during the first 18 weeks and then monthly).

Written informed consent was obtained before inclusion in the study. The Ethical Committees of the hospitals at which this study was carried out endorsed the study protocol.

Other PET results corresponding to this sample have been reported elsewhere. A comparison of cerebral metabolic patterns among the 34 TR patients included before receiving clozapine, and the same 17 NN patients and the healthy controls in the present sample has been reported [7]; Moreover, metabolic changes with risperidone are described in [29] by comparing no treatment vs. risperidone conditions in 11 patients included within the 17 in the present sample. Finally, a direct a comparison between pre- and post clozapine conditions in the same TR group in this sample (n=23) can be found in [28].

PET procedure

PET studies were performed with a Posicam EZL PET scanner 20 min after the injection of 370 MBq of 18-FDG. The matrix size was 256×256×61, and slices were 2.6 mm thick. Subjects were instructed to lie down in the supine position under twilight conditions in a silent room with their eyes open and ears unplugged for 10 minutes before FDG administration and for a further twenty minutes before image acquisition. They did not receive any special instructions but were asked to remain as relaxed as possible. The PET study was performed after a fasting period of more than six hours. Coffee and psychoactive beverages were disallowed.

Image analysis

PET images were analyzed with the SPM99 software package (from the Welcome Department of Cognitive Neurology, London, UK) [9]. The PET images were transformed into a Talairach stereotatic space [36], warping each scan to a reference FDG-PET template that already conformed to the standard space. This image was created using normal FDG-PET scans following the procedure described in [13], which proved to afford higher sensitivity in the later statistical analyses than the standard PET template included in the SPM99 package. Images were reformatted to a final voxel size of 2×2×2 mm and were smoothed using an isotropic Gaussian kernel of 12×12×12 mm FWHM. The grey level threshold was set at 0.8: i.e., only voxels with an intensity level above 0.8 of the mean level for the scan were included in the statistical analysis. Intensity normalization was carried out using proportional scaling, thus assuming that global brain metabolism was equal for every scan.

Statistics

Clinical data

Comparisons of clinical scores (SANS and SAPS items) between post-clozapine and NN patients were performed using t tests for independent samples. Comparisons of these scores within the group treated with clozapine (i.e., pre- and post-clozpaine) were made using t tests for related samples.

Metabolic data

These comparisons were performed using SPM99. Once the scans had been spatially normalized, the differences between groups were assessed by independently comparing voxel values and assigning a z score and a p value to the differences. The threshold for considering a change as being significant was set at p<0.001 (z score=3.09). To overcome the problem of multiple comparisons, we used peak-height corrected p values, based on distributional approaches from the theory of Gaussian fields [33].

According to this criteria, the TR groups were compared using one-tailed t tests, without including covariate effects such as age or sex, which were previously assessed as being non-significant. The alternative approach of using ANOVA was discarded because the assumption of homogeneity of variances did not hold for all the groups, and the t test is in fact more robust under these circumstances.

Setting the proper thresholds to consider an observed p value as significant is critical in this type of study [1]. Accordingly, we carried out a validation procedure to determine the most suitable level of significance for our data. Assuming that no significant differences would be found within the control group, we used a bootstrap (random sampling) technique to extract 200 random subgroups, for which we performed the same tests as in the patient groups [8]. This procedure provided empirical validation of the minimum significance level used throughout the study (p<0.001).

Based on our hypotheses, we compared the metabolic activity of the patients receiving clozapine with that of the controls and NN patients.

Results

There were no significant differences between groups in terms of age (F=2.11, df=2, p=0.13) or sex distribution (χ²=0.53, df=2, df=2, p=ns). From pre- to post-clozapine conditions, the severity of all positive symptoms, alogia and affective blunting significantly decreased (p<0.05 in all cases). Clozapine-treated patients showed significantly lesser delusion and hallucination scores than NN patients ([Table 1]). Concerning the global response 18 patients out of 23 who completed the follow-up showed at least a marked improvement with clozapine in the CGI scale

Activity differences between TR-clozapine treated patients and controls

In comparison with the controls, in this condition the clozapine-treated patients showed a marked hypofrontality, which was mainly significant in the dorsolateral, orbitofrontal and anterior cingulate cortices ([Table 2] [Fig. 1]). The insular cortex also showed a significantly lower activity than in the controls. At the subcortical level, the head of the right caudate nuclei was hypoactive in the patients receiving clozapine as compared to the controls.

Activity differentes between TR-clozapine treated and NN patients

When compared to the NN group, the clozapine-treated patients showed the same hypoactivity that they showed in comparison to the controls, in the anterior cingulate, bilateral orbitofrontal and dorsolateral cortices, and insula ([Table 3] [Fig. 2]).

Discussion

According to the present results, our schizophrenia patients showed a marked hypofrontality after receiving clozapine and at the same time showed a good clinical response.

Hypofrontality, as compared to the controls during clozapine administration, was not found in the same patients included in that study during haloperidol treatment as compared to the same controls [7], i.e., six months before. Moreover, essentially the same hypofrontality was observed in clozapine-treated patients with respect to NN patients, although no differences were found between the same TR patients prior to clozapine and the same NN group [7]. Thus, the effect in decreasing frontal activity seems to be directly attributable to clozapine; it cannot be due to the chronic stage in TR patients, since they did not show hypofrontality prior to clozapine treatment. These TR patients had been receiving haloperidol prior to clozapine, but the withdrawal of the former seems an unlikely factor to explain the observed hypofrontality, since haloperidol administration decreases cortical metabolism [4] [17].

The observation of frontal hypometabolism after clozapine administration is coherent with previous studies. First, Cohen et al. [4] reported that clozapine decreases metabolism in the superior and inferior prefrontal cortices during continuous performance tests. This is in remarkably good agreement with our findings under resting conditions. Second, studies using single-photon emission tomography have revealed that only responders to clozapine show a significant decrease in PF and thalamic activity as compared to a haloperidol baseline [26] [35]. Finally, Potkin et al. [34] have reported that responders to clozapine show a significant metabolic decrease in the cortex.

In the present work, we have not studied the association between metabolic changes and clinical response, previously reported for the same sample [28]. In that study we used a dimensional approach rather than categorizing patients into responders and non-responders, since the categories between response and non-response have the risk to classify into different groups patients with similar response rates. We reported no association between clinical and metabolic changes on the frontal lobe, which would indicate a similar decrease in responders and non-responders. In another work, aimed to predict the change in clinical scores with clozapine using structural and metabolic data before initiating that treatment we could not found any predictive value for basal frontal activity [31]. Taken together, these and the present results provide support for a “hypofrontalizing effect” of clozapine per se, that might be more or less beneficial from a clinical point of view depending on the presence of other cerebral problems.

The metabolic decrease in the PF region with clozapine is consistent with pre-clinical data. Clozapine increases extracellular dopamine in the prefrontal cortex [25] [42] and dopamine increases GABA release in the same region [14], this GABA release being coherent with a lower metabolic rate. From another perspective, the higher ratio of D1 to D2 blockade with clozapine vs. haloperidol [22] may also be relevant to the observed metabolic inhibition with clozapine. This ratio is also different in clozapine as compared to other atypical antipsychotics [37]. D1-type receptors are more densely distributed in the PF cortex, and their activation stimulates neuronal adenyl-cyclase [11]. It is therefore plausible that a higher degree of blockade of these receptors may contribute to the PF metabolic decrease observed with clozapine. Such a possibility would be consistent with an improvement in neuropsychological performance in schizophrenia, since D1 antagonists may enhance working memory [40]. From this perspective, it is interesting to note that both the metabolic changes with clozapine and the clinical changes seen with this drug have been found to be associated with a D1 receptor allele [34]. Alternatively, the increase of dopamine meditated by clozapine [25] [42] may stimulate D1 receptors in the cortex, and balance dopamine transmission from a D2-dominated state, proposed to be relevant for schizophrenia [41], to a more normal D1-dominated state.

The changes in activity with clozapine treatment seem to be clearly different from those induced by risperidone [24] [29] [37] and olanzapine [27]. Neither of these drugs induces such a marked decrease in frontal activity as clozapine. From this perspective, such a decrease could be a unique feature of clozapine.

A higher frontal metabolic deficit seems counterintuitive as a therapeutic mechanism in schizophrenia. Nevertheless, these patients had improved very significantly. From a speculative point of view, one explanation is that such an effect could compensate other problems in probably hyperactive regions in schizophrenia, where the frontal lobe exerts an excitatory effect. This may be the case of the limbic region, where frontal projections are direct and excitatory [3] [10] [8]. Indeed, limbic hyperactivity is a replicated finding in schizophrenia, and is related to psychotic symptoms [16] [21] [32]. Moreover, frontal hypoactivation with clozapine may also counteract the excessive subcortical release of dopamine in schizophrenia after stimulation [20], because the dopaminergic nuclei in the brainstem are partially controlled by frontal afferences [12]. These interpretations remain clearly speculative, given the design of our study. Other explanations may be also possible, since hypoactivation during cognitive activation has been shown to be related to excessive subcortical dopamine release in schizophrenia [23].

Among the limitations of the study, the PET scans were acquired under resting conditions. However, the agreement of the present results with those of Cohen et al. [6], obtained with a standard cognitive activation paradigm, lend support to the validity of our design. On the other hand, we cannot rule out the possibility that the observed metabolic decrease might facilitate the activation of discrete frontal regions involved in different cognitive tasks, as suggested by the results of Lahti et al [19]. In this latter report, increases in the activity in some subregions of the PF lobe were accompanied by metabolic decreases in other PF areas. Another limitation is the addition of the possible effects of chronicity to those of clozapine, which only could be avoided if we treated with clozapine NN patients, which is currently forbidden by the laws in our country. There were no significant differences in age, although TR patients were 5 years older than NN patients. However, the pattern of metabolic differences with that group was the same as the observed in comparison to healthy controls, and was not observed in the comparison between both patients groups reported elsewhere [7]. Finally, the lack of clozapine serum levels is also a limitation, as these levels might hypothetically correlate to the effects of that drug on brain metabolism and may be needed to assure compliance.

In conclusion, we have found support for the preferential prefrontal metabolic action of clozapine in the schizophrenic brain, resulting in a clearly hypofrontal state as compared to controls.

Acknowledgements

Supported in part by a grant from the Fondo de Investigaciones Sanitarias (98/1083).

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Correspondence

V. MolinaPhD 

Department of Psychiatry

Hospital Clínico Universitario

Paseo de San Vicente 58-182

37007 Salamanca

Spain

Phone: +34/923/29 11 02

Fax: +34/923/29 13 83

Email: vmolina@usal.es

References

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Correspondence

V. MolinaPhD 

Department of Psychiatry

Hospital Clínico Universitario

Paseo de San Vicente 58-182

37007 Salamanca

Spain

Phone: +34/923/29 11 02

Fax: +34/923/29 13 83

Email: vmolina@usal.es