Antipsychotics have been a field of intense study for the past 70 years, but there’s still a need for better medications to target the negative symptoms and cognitive impacts of schizophrenia.

In addition to more drug innovation, a better understanding of how to use the drugs currently available—including their dose, dosage, and drug alternatives—is needed.

 

Dose and dosages

Authors of a review published in Schizophrenia Bulletin highlighted evidence concerning dosing.

Takeuchi H, Leucht S, Kane JM, et al. Antipsychotic medications: Enhancing use to improve outcomes. Schizophr Bull. 2021;47(5):1201–1204.

 

They noted that the debate regarding maintenance dosing is contentious, and discontinuation remains a major barrier to effective treatment. Consequently, maintenance dosing can contribute to relapse. No established variables predict antipsychotic discontinuation. Intermittent or targeted antipsychotic interventions are also linked to relapse compared with maintenance treatments.

To surmount this, injectable alternatives may be considered.

Paliperidone palmitate (Invega) is an FDA-approved long-acting injectable antipsychotic (LAI). LAIs outperform oral antipsychotics in terms of decreasing relapse/rehospitalization, according to research. These improvements may be linked to improved functioning. However, a higher frequency of relapse leads to a worsening of active psychosis, and long-term functionality diminishes.

Results from a real-world, observational, prospective study published in Expert Opinion in Pharmacotherapy indicated that in patients with schizophrenia, paliperidone palmitate predicted enhancements in social functioning, as well as symptom stability.

Garcia-Portilla MP, Benito Ruiz A, Gómez Robina F, et al. Impact on functionality of the paliperidone palmitate three-month formulation in patients with a recent diagnosis of schizophrenia: A real-world observational prospective study. Expert Opin Pharmacother. 2022;23(5):629–638.

The drug was well-tolerated, and patients were pleased with it.

 

Antipsychotics are routinely prescribed once daily if the plasma half-life is greater than 24 hours, or in divided dosing if the plasma half-life is less than 24 hours. Research exploring dopamine D2 receptor occupancy and antipsychotic blood concentrations indicated that peripheral pharmacokinetics are different from central pharmacokinetics, with a slower reduction of concentrations centrally.

In other words, there is increased dopamine D2 occupancy centrally. Once-daily dosing is not necessarily inferior to divided dosing, and often results in a lower burden of adverse effects, such as sleepiness.

It’s best to take these medications before bed due to their potential sedative effects, a strategy that could possibly enhance adherence and outcomes.

 

Switching meds

When treating patients, psychiatrists commonly switch among different antipsychotics, but this practice has lacked a definitive evidence base. It’s unclear, for example, whether these agents should be abruptly discontinued, reduced over time, or tapered after a new antipsychotic has been introduced.

One argument in favor of tapering has been concerns over dopamine supersensitivity psychosis. The presence of decreased clearing of dopamine centrally, however, counterbalances such concerns.

Meta-analyses demonstrate no difference between immediate discontinuation, tapering, or wait-and-taper approaches. Also, these approaches don’t differ in their risk of adverse effects including dopamine-linked withdrawal. These findings suggest that immediate discontinuation is best.

 

What can be done

Careful consideration should be given to the pharmacologic properties of antipsychotics and clinical characteristics of the patient such as smoking or pharmacogenetics, which can alter pharmacokinetics.

In global terms, new agents need to be developed according to the review in Schizophrenia Bulletin. “Unfortunately, the nature of schizophrenia also translates to rates of progress that are slower than what we would wish,” the authors wrote. “As we await these advances, it is no less important to ensure optimization of all treatments we currently have in hand.”

In the case of pharmacotherapy, decades of use may have lulled us into thinking that we know how to use these drugs, and this is not the case.

One issue warranting further examination is the heterogeneity of schizophrenia populations, according to an article published in Frontiers in Psychiatry.

Weston-Green K. Antipsychotic drug development: From historical evidence to fresh perspectives. Front Psychiatry. 2022;13:903156.

 

“In light of the existence of sub-populations and heterogeneity in schizophrenia, developing a better understanding of the basic science and pharmacological mechanisms of potential novel therapeutics prior to initiating clinical trials may inform a more targeted approach to likely responders,” the author wrote.

Specifically, investigators are currently questioning the importance of P values when there are varied populations; even nonsignificant efficacy may prove worthwhile (ie, some benefit is better than none).

With drugs like antipsychotics, researchers should probably not be beholden to P values, and should instead consider them as they were intended—as a suggestive or hypothesis-generating measure.