The Effect of Olanzapine Treatment on Monoamine Metabolite Concentrations in the Cerebrospinal Fluid of Schizophrenic Patients

Abstract

The mechanism of action of both typical antipsychotics and the atypical antipsychotic, clozapine, may be related to the (changing) interaction of dopamine and serotonin in schizophrenia. This study examined the effect of olanzapine in schizophrenic patients on cerebrospinal fluid (CSF) metabolites of dopamine (homovanillic acid, HVA) and serotonin (5-hydroxyindoleacetic acid, 5-HIAA). Twentythree male schizophrenic patients, who were drug-free for at least 2 weeks (mean drug-free period of 35 days Ϯ 43; median 16 days), underwent a lumbar puncture (LP).Patients were subsequently treated with olanzapine 10 mg/ day for 6 weeks, after which the LP was repeated. CSF was assayed for It has long been postulated that the mechanism of action of antipsychotics is related to their ability to block dopamine 2 (DA 2 ) receptors (Creese et al. 1976; Carlsson 1978; Farde et al. 1988). However, since the introduction of the atypical antipsychotics, most notably clozapine, it has become clear that DA 2 receptor blockade alone is insufficient to explain the clinical potency of all antipsychotic drugs (Meltzer 1989; Davis et al. 1991;Lieberman et al. 1998). Instead, it has been proposed that the mechanism of action of antipsychotics is rooted in their ability to affect both DA and serotonin (5-hydroxytryptamine, 5-HT) systems in the brain or, more specifically, their interaction (Meltzer 1989;Hsiao et al. 1993a;Kahn et al. 1993;Szymanski et al. 1993;Schmidt et al. 1995;Kapur and Remington 1996;Lieberman et al. 1998). Indeed, DA and 5-HT are functionally (Agren et al. 1986;Risby et al. 1987;Kelland et al. 1990;Roth and Meltzer 1995;Iyer and Bradberry 1996;Lieberman et al. 1998;) and anatomically (Ternaux et al. 1977;Priestley et al. 1981;Hetey and Drescher 1986; Fibiger and Miller 1987;Törk 1991) 25 , NO . 4 The Effect of Olanzapine on HVA and 5-HIAA in CSF 469One way to examine DA and 5-HT systems in the brain is through measurement of their metabolites in cerebrospinal fluid (CSF), that is, homovanillic acid (HVA) and 5-hydroxyindole-acetic acid (5-HIAA), respectively. Several studies (Garelis and Sourkes 1973;Weir et al. 1973;Wood 1980;Andersen et al. 1981; Bertilsson et al. 1982;Stanley et al. 1985;Wester et al. 1990; cf. Banki and Molnar 1981;Potter and Manji 1993) have demonstrated that concentrations of HVA and 5-HIAA in CSF reliably reflect HVA and 5-HIAA concentrations in the brain. This suggests that CSF HVA and 5-HIAA concentrations reflect central DA and 5-HT turnover and thus can be used to examine the effects of antipsychotic drugs on these two neurotransmitters and their ratio in vivo (Agnati et al. 1995;Silver et al. 1996).It has been shown that typical antipsychotics, which predominantly block DA 2 receptors, increase CSF HVA concentrations (Wode-Helgodt et al. 1977; Härnryd et al. 1984;Sharma et al. 1989;Hsiao et al. 1993b;Kahn et al. 1993;Wieselgren and Lindstrom 1998;) and the HVA/5-HIAA ratio (Wode-Helgodt et al. 1977; Härn-ryd et al. 1984;Hsiao et al. 1993b;Kahn et al. 1993) without significantly ...

Serotonin and Schizophrenia

“…Additionally, while 5-HIAA and HVA levels alone could not predict treatment outcome, a low HVA/5-HIAA CSF ratio was significantly associated with better response to clozapine and typical antipsychotics in several studies (Pickar et al, 1992;Kahn et al, 1993a;Risch and Lewine, 1993;Szymanski et al, 1993;Lieberman et al, 1994;Risch, 1995). These results suggested that the antipsychotic effect is associated with changing dopamine function relative to 5-HT function, rather that changing dopamine or 5-HT function per se (Scheepers et al, 2001b).…”

“…But all of these measure have been found to be associated with decreased HVA CSF levels as well (ibid. ; Scheepers et al, 2001b).…”

“…However, at least two studies failed to find a predictive value of the HVA/5-HIAA CSF ratios regarding treatment response to olanzapine, clozapine, or haloperidol treatment (Jacobsen et al, 1997;Scheepers et al, 2001b), while one study reported a worse long-term outcome in patients with a low HVA/5-HIAA CSF ratio (Wieselgren and Lindstrom, 1998). These discrepancies may be explained due to differences in patient populations, duration of treatment, method of analysis, or criteria of response.…”

“…Surprisingly, several investigations demonstrated that neither typical nor atypical antipsychotics changed 5-HIAA CSF levels in the course of treatment, although many of these substances strongly affect the 5-HT system (van Kammen et al, 1986;Kahn et al, 1994;Jacobsen et al, 1997;Wieselgren and Lindstrom, 1998;Scheepers et al, 2001b). These results put the idea somewhat into question that 5-HIAA CSF concentrations are a valid marker of the central 5-HT turnover.…”

“…These results put the idea somewhat into question that 5-HIAA CSF concentrations are a valid marker of the central 5-HT turnover. Moreover, it was suggested that 5-HIAA concentrations may not mirror 5-HT metabolism in the whole brain but rather reflect turnover in specific brain regions such as frontal cortices and the striatum (Scheepers et al, 2001b). On the contrary, typical antipsychotics seem to consistently elevate HVA CSF levels and HVA/5-HIAA CSF ratios, while atypical substances did not Kahn et al, 1993a;Wieselgren and Lindstrom, 1998;Scheepers et al, 2001b).…”