Experimental Studies on Novel Pharmacological Strategies in the Treatment of Schizophrenia

The modified dopamine (DA) hypothesis of schizophrenia suggests a hyperdopaminergic state in subcortical brain regions, which is believed to cause positive symptoms, while cortical regions may show a hypodopaminergic state which is believed to generate negative and cognitive symptoms. Positive symptoms are improved by typical antipsychotic drug (APD) treatment. However, negative and cognitive symptoms remain less affected. Typical APD treatment is often associated with extrapyramidal side effect (EPS) liability due to high DA D2 receptor blockage (≥80%). In comparison with typical APDs, atypical APDs may show better clinical efficacy, e.g. the atypical APD clozapine shows superior efficacy in treatment-resistant schizophrenia in terms of its ability to improve negative symptoms and some aspects of cognitive impairment with an absence of EPS liability, due to its low DA D2 receptor occupancy (about 45%). Contrary to typical APDs, clozapine and other atypicals increase cortical DA release in experimental animals. This effect is thought to be underlying its ability to improve negative and cognitive symptoms. However, clozapine may increase the risk for agranulocytosis and also, similar to some other atypicals, cause weight gain and sedation. Since the severity of cognitive impairment in schizophrenia is a critical determinant of treatment outcome, it is important to find alternative pharmacological strategies with better clinical efficacy and fewer side effects than available APDs. Thus, several drug treatment strategies have been applied clinically in order to achieve this goal. For example, earlier clinical studies have shown that adjunctive low doses of L-dopa to typical APDs improve negative symptoms in schizophrenic patients. Recently, it has been reported that adjunctive treatment with the antiepileptic drug topiramate may improve the effect of APDs, especially against negative symptoms, when used in schizophrenic patients maintained on a stable APD medication. Thus, we here examined experimentally these clinical findings, by investigating the effects of adjunctive treatment with either a low dose of L-dopa or topiramate to low doses of the selective DA D2 receptor antagonist raclopride using the conditioned avoidance response (CAR) paradigm for evaluating antipsychotic activity. EPS liability was assessed by means of the catalepsy test. Using microdialysis, DA output was assessed in the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAC), respectively following these drug combinations. We found that adjunct low dose L-dopa or topiramate markedly augmented the antipsychotic-like effect of a low dose of raclopride in CAR. This augmentation was associated with a significant increase in DA output in the mPFC, but with a smaller increase in DA release in the NAC, and without catalepsy. Our experimental results support previous clinical findings that adjunctive treatment with low doses of L-dopa or topiramate to typical APD treatment may augment therapeutic efficacy in schizophrenia and with lower risk of EPS. These results are in line with our previous finding showing enhanced cortical DA output and antipsychotic-like effect of raclopride by adjunct α2 adrenoceptor blockage and indicate the possibility to augment typical APDs with an absence of severe side effects. Taken together, we conclude that an enhanced prefrontal DA output per se may serve to improve the effect of typical APDs in schizophrenia. Clinical studies have shown that selective serotonin reuptake inhibitors (SSRIs) may, at high doses, induce Parkinsonism in sensitive individuals. However, preclinical studies have revealed that stimulation of 5-HT1A receptors may modulate typical APD-induced catalepsy. Thus, it has been hypothesized that stimulation of 5-HT1A receptors may protect against an inherent potential for parkinsonism of SSRIs. Here, we evaluated the possible risk of EPS following the combined treatment with a high dose (40 mg/kg) of the SSRI citalopram and the selective 5HT1A receptor antagonist WAY 100635 using catalepsy. We observed significant catalepsy following this drug combination, while the drugs were ineffective when given alone, indicating that catalepsy, even without any direct DA D2 receptor blockade, can be induced by SSRIs together with 5-HT1A receptor blockade. This effect may be related to enhanced inhibition of dopaminergic, particularly nigrostriatal, activity and may be mediated via 5-HT receptor subtypes other than the 5-HT1A. Since we showed that a high dose of citalopram/WAY100635 in combination produced significant catalepsy; and because catalepsy and suppression of CAR behavior are thought to be mediated via suppression of dopaminergic neurotransmission, we investigated the potential antipsychotic activity of combined treatment with lower doses (10 or 20 mg/kg) of citalopram and WAY100635 in CAR. EPS liability was also evaluated using catalepsy. Combined treatment with citalopram (20 mg/kg) and WAY100635 produced a significant antipsychotic-like effect as revealed by CAR and without producing significant catalepsy. The two drugs were ineffective when given alone. Pretreatment with the selective 5-HT2C receptor antagonist SB242084 completely prevented the citalopram/WAY100635-induced effect on CAR, indicating a specific involvement of the 5-HT2C receptor in the antipsychotic-like effect observed. The effect on CAR by this treatment combination is similar in magnitude to that of a moderate dose of the typical APD haloperidol. Our data suggests a novel treatment option for individuals suffering from e.g. psychotic depression. In conclusion, our studies provide experimental support for previous clinical findings and also suggest novel mechanisms that could be exploited to improve pharmacotherapy of schizophrenia.