Clozapine and Treatment-Refractory Illness
Ragy R. Girgis, Gary Brucato, Jeffrey A. Lieberman in Understanding and Caring for People with Schizophrenia, 2020
Despite all these potential side effects, which range from mild and common to rare and life-threatening, clozapine remains definitively superior to other antipsychotic medications for treatment-refractory conditions. Because of all these potential side effects, however, clozapine is also sorely underutilized. Many patients and families are discouraged by the potential side effects, if not downright frightened of them, or else simply do not want the burden of having their blood drawn every week. Many providers have limited experience with clozapine and/or are too worried about litigation arising from a patient developing a severe side effect. Therefore, while clozapine is every bit a potential miracle drug for many people with schizophrenia, it is also emblematic of the challenges faced every day by patients, families, and providers.
Spice Drugs, Synthetic Cannabinoids, and ‘Spiceophrenia’
Ornella Corazza, Andres Roman-Urrestarazu in Handbook of Novel Psychoactive Substances, 2018
In the literature, there are controversial views on the treatment of substance-related/‘dual’ psychotic disorders. Although, according to San et al. (San, Arranz, & Martinez-Raga, 2007), second-generation antipsychotics may confer some advantages over first-generation antipsychotics, for the treatment of substance-induced psychotic disorders, other authors found no evidence of better outcomes with second-generation antipsychotics (Petrakis, Leslie, Finney, & Rosenheck, 2006). Furthermore, other studies found that both clozapine and olanzapine may present distinct advantages in reducing substance-induced psychotic symptoms without increasing craving in patients with concomitant cannabis-use disorders in comparison to patients treated with risperidone (MacHielsen et al., 2012; Machielsen, Veltman, van den Brink, & de Haan, 2018). Finally, clozapine has been reported to reduce substance misuse and improve psychosis, potentially ameliorating the dysfunction within the dopamine-mediated brain reward circuitry implicated in addiction (Green, Noordsy, Brunette, & O’Keefe, 2008). Additionally, second-generation antipsychotics act as antagonists at serotonin 5-HT2A receptors, the main target of most hallucinogenic drugs (Papanti et al., 2018; Valeriani et al., 2015). Further studies clearly need to be carried out to clarify these treatment and management issues.
Agitation and Psychosis
Marc E. Agronin in Alzheimer's Disease and Other Dementias, 2014
Sometimes three or more agents are used. Combining two or more antipsychotics or multiple benzodiazepines should be avoided because of the increased risk of side effects. Clozapine is usually the medication of last resort (Lee et al., 2007). In intensive care settings, intravenous haloperidol has also been used with success. However, a dose-related risk of ventricular arrhythmias, specifically torsade de pointes, must be kept in mind, and it may necessitate the use of cardiac monitoring (Meyer-Massetti et al., 2010). Electroconvulsive therapy is indicated when the presence of treatment-resistant mania or psychotic depression is suspected, but it may also be considered for severe agitation that does not clearly fit into any category (Ujkaj et al., 2012). When all other strategies have failed to control severe agitation, the clinician should consider moving the individual to a more structured setting, such as a dementia unit or a psychiatric hospital, for more intensive behavioral and pharmacologic management.
Update on novel antipsychotics and pharmacological strategies for treatment-resistant schizophrenia
Published in Expert Opinion on Pharmacotherapy, 2022
Andrea de Bartolomeis, Mariateresa Ciccarelli, Licia Vellucci, Michele Fornaro, Felice Iasevoli, Annarita Barone
According to the guidelines, clozapine should be offered after the failure of at least two adequate antipsychotic trials, including at least one with a long-acting injectable drug [5,37]. On the other hand, the probability of non-response to the first antipsychotic administered has been found to be similar to that with a second different antipsychotic. Thus, it is possible to hypothesize a treatment-resistance condition on the basis of a single course of antipsychotic treatment [38]. In this regard, the results of the OPTiMiSE study supported the strategy of switching clozapine also in patients with first-episode schizophrenia who do not respond to their initial antipsychotic treatment [39]. With respect to secondary acquired forms of resistance, the prevention of multiple relapses of the disease as well as of tardive dyskinesia and supersensitivity psychosis should be emphasized [15,37,40]. For instance, measures to be observed include ensuring proper adherence, avoiding abrupt discontinuation, under-dosing or too short duration of therapy, early detection of extrapyramidal symptoms (EPS) or elevation in prolactin levels, prescribing the lowest effective dose of antipsychotic during maintenance, preventing substance abuse [40].
A systematic review of maternal and infant outcomes after clozapine continuation in pregnancy
Published in International Journal of Psychiatry in Clinical Practice, 2022
Ramya Thanigaivel, Reece Bretag-Norris, Andrew Amos, Brett McDermott
Clozapine is considered a category C drug by the Therapeutic Goods Administration of Australia (Therapeutic Goods Administration 2020), described as a drug which ‘owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human foetus or neonate without causing malformations’. The literature available to guide management of pregnancy amongst women already treated with clozapine is limited, comprising mostly case series and case reports (Abel 2002; Teodorescu et al. 2017). This hinders clinical application of the risk category to real life management of patients requiring antipsychotic treatment during pregnancy. Pharmacovigilance data of all suspected adverse drug reactions during pregnancy reported to the World Health Organisation, comprising ∼200,000 safety reports, does not suggest that clozapine is less safe during pregnancy than other antipsychotics (Beex-Oosterhuis et al. 2020). As women on clozapine maintenance have had unsatisfactory responses to other antipsychotics, the decision whether to continue clozapine in patients who become pregnant is critical. This systematic review was designed to evaluate the evidence on adverse maternal and infant outcomes after clozapine continuation to facilitate cost/benefit analyses for treatment resistant women.
New approaches to antipsychotic medication adherence – safety, tolerability and acceptability
Published in Expert Opinion on Drug Safety, 2022
Sharon Taub, Amir Krivoy, Eromona Whiskey, Sukhi S. Shergill
Traditionally, clozapine is available for oral administration only and has no long-acting pharmaceutic formulation. Hence, there are practical difficulties to prescribe oral clozapine for severe schizophrenia patients in their acute, agitated, psychotic state, who are often less cooperative with oral treatment. Yet, this subgroup of patients is the most likely to benefit from clozapine in the long term. A retrospective clinical study recently published [46] assessed effectiveness of short-acting intramuscular (IM) clozapine treatment. Thirty-nine initially nonadherent patients treated with clozapine injections were compared with a cohort of 162 patients treated with oral clozapine exclusively. All participants were inpatients diagnosed with treatment-refractory psychosis. Almost all (92%) of the IM clozapine patients later agreed to switch to oral formulation, and 76% of them remained on clozapine after 2-year follow-up period. Clozapine discontinuation rates were similar in both groups. The authors conclude that IM clozapine can be effectively used as a temporary bridge for long-term oral clozapine administration.
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