Antipsychotics, the heartland of clinical psychopharmacology?

Clinicians of a certain vintage will recall discussion about the ‘heartland’ of psychiatry; the predominant view being that, ‘schizophrenia’, in all its myriad forms, should be the focus of clinical services and research, with others countering that bipolar disorder, arguably a more important disorder, had often been neglected particularly within British psychiatry (Goodwin and Geddes, 2007). Is there a similar heartland for clinical psychopharmacology? Some may assume, due to their widespread use and clear efficacy, that antidepressants are the heartland of psychopharmacology (McAllister-Williams, 2008; Young and Moulton, 2020). We would, however, argue that this term has been considered de facto to apply to the ‘antipsychotics’. The term ‘antipsychotic’ itself is archaic, stating their heterogenous effects with many neurotransmitter systems involved in different degrees. Mirroring the above bias seen in clinical psychiatry, antipsychotics are still associated with schizophrenia, despite evidence of efficacy of different antipsychotics across a range of psychiatric disorders. This likely reflects their differing pharmacological properties, and is illustrated by their being licensed in bipolar disorder (Jauhar and Young, 2019) and as adjunctive treatments in depression (Rafeyan et al., 2020; Wang et al., 2016). In fact, if one reads through the description of people, who received chlorpromazine in one of the initial trials conducted by Delay et al. (1952), a high proportion probably had an affective psychosis. Furthermore, one of the first observational studies of antipsychotics in maintenance treatment appears to be the use of clozapine (a drug now associated primarily with schizophrenia) in people attending a service for resistant mood disorders (Zarate et al., 1995). Therefore, the piece by Reynolds (2021), making the case for considering these medications on a more individual basis in most time, especially the partial agonists, which include aripiprazole, brexiprazole and cariprazine. Guidelines are necessary, though the current guidance which constitutes high-dose antipsychotics probably reflects excessive dosing of first generation antipsychotics which was seen all too often in the past, neglecting knowledge on D2 receptor occupancy and antipsychotic response (Kapur, 2000). In clinical practice partial agonists mitigate hyper-prolactinaemia and have a clear evidence-base, and there is little doubt that this should be incorporated into guidance? This edition of the journal has many papers concerning antipsychotics and ‘psychosis’. Besag et al. (2021) report a systematic review of the pharmacological treatment of Tourette syndrome in children and adults. This interesting review identified randomised, placebo-controlled trials of aripiprazole, risperidone, clonidine, guanfacine, haloperidol, pimozide, tiapride and sulpiride for the treatment of tics in children and adults with Tourette syndrome (Besag et al., 2021). They concluded that there are currently few placebo-controlled trials to support the efficacy of most commonly used pharmacological treatments. Clonidine and guanfacine are better tolerated than antipsychotics, but less effective. There is currently too little evidence to determine whether adults respond differently from children. Although pharmacological interventions frequently achieve satisfactory short-term efficacy, the evidence of the medication for the best long-term solution remains questionable. An interesting systematic review conducted by de Filippis et al. (2021) based on a search for reports of clozapine related reactions and concluded that although clozapine-related drug reaction with eosinophilia and systemic symptoms may be rare, it may also be under-reported. Forte et al. (2021) also reviewed clozapine and compared it to other drugs used for psychosis, including aripiprazole, olanzapine, risperidone, quetiapine and ziprasidone. They found that, based on available data, clozapine was unique in its ability to reduce the risk of completed suicides and attempts in schizophrenia patients (Forte et al., 2021). This effect did not appear to be shared with other modern drugs for psychosis or apply in disorders other than chronic psychotic illnesses. Further studies are needed to quantify the anti-suicidal effect of modern drugs for psychosis effective in treating bipolar disorder (lithium has clear evidence of anti-suicidal actions). Antipsychotics, the heartland of clinical psychopharmacology?