Abstract
Antipsychotic drugs represent the most effective treatment for chronic psychotic disorders. The newer second generation drugs offer the advantage of fewer neurological side-effects compared to prior drugs, but many cause serious metabolic side-effects. The underlying physiology of these side-effects is not well-understood, but evidence exists to indicate that the sympathetic nervous system may play an important role. In order to examine this possibility further, we treated separate groups of adult female rats acutely with either the first generation antipsychotic drug haloperidol (0.1 or 1 mg/kg) or the second generation drugs risperidone (0.25 or 2.5 mg/kg), clozapine (2 or 20 mg/kg), olanzapine (3 or 15 mg/kg) or vehicle by intraperitoneal injection. Blood samples were collected prior to drug and then 30, 60, 120, and 180 mins after treatment. Plasma samples were assayed by HPLC-ED for levels of norepinephrine, epinephrine, and dopamine. Results confirmed that all antipsychotics increased peripheral catecholamines, although this was drug and dose dependent. For norepinephrine, haloperidol caused the smallest maximum increase (+158%], followed by risperidone (+793%), olanzapine (+952%) and clozapine (+1,684%). A similar pattern was observed for increases in epinephrine levels by haloperidol (+143%], olanzapine (+529%), risperidone (+617%) then clozapine (+806%). Dopamine levels increased moderately with olanzapine [+174%], risperidone [+271%], and clozapine [+430%]. Interestingly, levels of the catecholamines did not correlate strongly with each other prior to treatment at baseline, but were increasingly correlated after treatment as time proceeded. The results demonstrate antipsychotics can potently regulate peripheral catecholamines, in a manner consistent with their metabolic liability.
Highlights
The second generation antipsychotic drugs represent the most effective pharmacological treatment for chronic psychotic illnesses, which include the schizophrenia spectrum disorders [1]
Observation of the chromatograms demonstrated that peaks for norepinephrine, epinephrine, and dopamine were all well-separated and with no overlap (Figure 1)
Post-hoc analysis revealed that both doses of risperidone caused a significant increase in norepinephrine levels by 30 mins compared to controls, but by 60 mins the lower dose of risperidone did not differ from controls, for the duration of the test (Figure 2A)
Summary
The second generation antipsychotic drugs ( known as the “atypical” antipsychotics, to differentiate them from the original first generation, “typical,” antipsychotics) represent the most effective pharmacological treatment for chronic psychotic illnesses, which include the schizophrenia spectrum disorders [1]. This class of drugs is increasingly being used to treat. The second generation drugs, have been linked to their own serious side-effects as well These most commonly include cardiometabolic side-effects, which significantly increase the risk of developing cardiometabolic disorders such as Type 2 diabetes mellitus (DM) and cardiovascular disease [11,12,13,14,15,16,17,18,19]. It is important to note, though, that these metabolic side-effects vary considerably between the different second generation antipsychotics, with some drugs having more severe metabolic effects than others [23, 24]
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