Clozapine as a drug of dependence

Goudie, Andrew J.; Smith, Judith A.; Robertson, Alex; Cavanagh, Clare

doi:10.1007/s002130050901

Cited by 23 publications

(17 citation statements)

References 33 publications

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“…Unlike the atypical antipsychotic drugs (APDs) (Goudie, et al, 2007; Goudie, et al, 1999) and non-selective NT agonists, such as NT69L (Tyler-McMahon, et al, 2000), which cause a large (−4.5°C) and long-lasting (>4 h) drop in body temperature, NT79 caused only a mild decrease (−1.5°C) in body temperature. The drop in body was transient and returned to baseline 1 h post-injection (Figure 1).…”

Section: Resultsmentioning

confidence: 99%

NT79: A novel neurotensin analog with selective behavioral effects

et al. 2010

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Neurotensin, a tridecapeptide, is widely distributed in the brain and gastrointestinal tract. It possesses analgesic, hypothermic, and antipsychotic-like properties. Neurotensin's effects are mediated mainly through two receptor subtypes, NTS1 and NTS2. Activation of NTS1 has been implicated in most of the pharmacological effects of neurotensin, but is associated with hypothermia and hypotension. We report on a novel neurotensin analog with higher selectivity to NTS2, namely, NT79 which exhibits selective behavioral effects.NT79 was tested in animal models for pain (thermal -hot plate test; visceral -acetic acid-induced writhing test), and in animal models that are predictive of antipsychotic-like effects (apomorphineinduced climbing; d-amphetamine-induced hyperactivity; disruption of prepulse inhibition). Its effects on body temperature and on blood pressure were also determined. Neurochemical changes in extracellular neurotransmitters were measured using in vivo microdialysis while the rats were simultaneously evaluated for acetic acid-induced writhing with and without pretreatment with NT79.Binding data at molecularly-cloned hNTS1 and hNTS2 suggest selectivity for hNTS2. NT79 blocked the acetic acid-induced writhing with an ED 50 of 0.14μg/kg, while having no effect on thermal nociception. The writhing was paralleled by an increase in 5-HT which was attenuated by NT79. NT79 demonstrated antipsychotic-like effects by blocking apomorphine-induced climbing, damphetamine-induced hyperactivity, and reducing d-amphetamine-and DOI-induced disruption of prepulse inhibition. Uniquely, it caused no significant hypothermia and was without effect on blood pressure. NT79, with its higher selectivity to NTS2, may be potentially useful to treat visceral pain, and psychosis without concomitant side effects of hypothermia or hypotension.

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Section: Resultsmentioning

confidence: 99%

NT79: A novel neurotensin analog with selective behavioral effects

et al. 2010

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“…Previous work suggests that CLZ tolerance isre lated to the withdrawal symptoms seen with the discontinuation of CLZ use (e.g. nausea, vomiting, insomnia, diarrhoea, agitation, aggression, headache, etc) [48] and relapse to psychosis [49, 50]. Thus the environmental and behavioral controls of its induction and expression as evidenced in these two preclinical tests may indicate that the appearance of CLZ withdrawal syndromes is also subjected to the same modulation by various environmental and behavioral factors.…”

Section: Discussionmentioning

confidence: 99%

Environmental and behavioral controls of the expression of clozapine tolerance: Evidence from a novel across-model transfer paradigm

Feng

Song

2013

Behavioural Brain Research

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Repeated administration of antipsychotic drugs induces a sensitization-like or tolerance-like effect in many behavioral tasks, including the conditioned avoidance response (CAR) and the phencyclidine (PCP)-induced hyperlocomotion, two rodent models with high predictive validity for antipsychotic activity. This study investigated the impacts of contextual and behavioral variables on the expression of clozapine tolerance using a recently validated across-model transfer paradigm (Zhang and Li, 2012). Male Sprague-Dawley rats were first repeatedly treated with clozapine (2.5–10.0 mg/kg, sc) in the CAR model or PCP (1.6 mg/kg, sc)-induced hyperlocomotion model for five consecutive days. They were then tested for the expression of clozapine tolerance in another model for another five days. Finally, all rats were switched back to the original model and tested again for the expression of clozapine tolerance. When tested in the PCP model, rats previously treated with clozapine in the CAR model did not show an immediate weaker inhibition of PCP-induced hyperlocomotion than those treated with clozapine for the first time, but showed a significantly weaker inhibition over time. In contrast, when tested in the CAR model, rats previously treated with clozapine in the PCP model showed an immediate weaker disruption of avoidance response than those treated with clozapine for the first time, but this weaker effect diminished over time. These results suggest that the expression of clozapine tolerance is strongly modulated by the test environment and/or selected behavioral response. Clozapine tolerance and its situational specificity may be related to the drug’s low extrapyramidal motor side effect, its superior therapeutic efficacy and/or emergence of clozapine withdrawal syndrome.

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“…Withdrawal from psychiatric medications, including antidepressants and antipsychotics, is associated with distinctive withdrawal or discontinuation syndromes, which are suppressed by resumption of the drug (Judah et al 1961; Lejoyeux & Ades 1997). Within different drug classes, drugs with a short half-life (including paroxetine, venlafaxine, and clozapine) typically provoke the most intense withdrawal symptoms (Goudie et al 1999; Hindmarch et al 2000). Users own reactions’ to the pharmacological effects of long-term drug use and subsequent withdrawal add another layer of consequences.…”

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confidence: 99%

The Psychoactive Effects of Psychiatric Medication: The Elephant in the Room

Cohen

Porter

2013

Journal of Psychoactive Drugs

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The psychoactive effects of psychiatric medications have been obscured by the presumption that these medications have disease-specific actions. Exploiting the parallels with the psychoactive effects and uses of recreational substances helps to highlight the psychoactive properties of psychiatric medications and their impact on people with psychiatric problems. We discuss how psychoactive effects produced by different drugs prescribed in psychiatric practice might modify various disturbing and distressing symptoms, and we also consider the costs of these psychoactive effects on the mental well-being of the user. We examine the issue of dependence, and the need for support for people wishing to withdraw from psychiatric medication. We consider how the reality of psychoactive effects undermines the idea that psychiatric drugs work by targeting underlying disease processes, since psychoactive effects can themselves directly modify mental and behavioral symptoms and thus affect the results of placebo-controlled trials. These effects and their impact also raise questions about the validity and importance of modern diagnosis systems. Extensive research is needed to clarify the range of acute and longer-term mental, behavioral, and physical effects induced by psychiatric drugs, both during and after consumption and withdrawal, to enable users and prescribers to exploit their psychoactive effects judiciously in a safe and more informed manner.

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Clozapine as a drug of dependence

Cited by 23 publications

References 33 publications

NT79: A novel neurotensin analog with selective behavioral effects

NT79: A novel neurotensin analog with selective behavioral effects

Environmental and behavioral controls of the expression of clozapine tolerance: Evidence from a novel across-model transfer paradigm

The Psychoactive Effects of Psychiatric Medication: The Elephant in the Room

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