Update on novel antipsychotics and pharmacological strategies for treatment-resistant schizophrenia

ABSTRACT

Introduction

Treatment resistant schizophrenia (TRS), the lack of response to at least two antipsychotics administered at adequate dose and duration, epitomizes in psychiatry one of the most difficult-to-treat pathologies, epidemiologically relevant (affecting one-third of schizophrenia patients) and with severe consequences for the patients in terms of overall functioning. After 50 years, only one drug is approved for TRS: clozapine. Furthermore, a few patients do not respond even to clozapine and are indicated as clozapine-resistant patients.

Areas covered

In this review and expert opinion, we have critically appraised the current literature, discussing the role of old and new agents in treating resistant schizophrenia.

Expert opinion

The search for therapy against TRS, beyond clozapine or in addition to clozapine, has emerged over time, capturing mainly three types of strategies: 1. Add-on of a second-generation antipsychotic (i.e. amisulpride); 2. Add-on of a second antipsychotic with significantly different receptor profile compared to the older ones (e.g. aripiprazole and cariprazine); 3. Novel strategies beyond dopamine D2/D3 receptor occupancy (e.g. xanomeline + trospium, TAAR1-agonists, sodium benzoate, and D-amino acids). More high-quality clinical trials applying the current operationalized criteria for TRS and clozapine-resistance are required to evaluate the efficacy of alternative and add-on treatments.

KEYWORDS:

• clozapine augmentation
• clozapine
• antipsychotics
• treatment resistant schizophrenia
• refractory psychosis

Article highlights

• Treatment-resistant schizophrenia (TRS) is a severe and epidemiologically relevant psychiatric condition affecting almost 30% of patients; clozapine represents the only available antipsychotic drug with the specific indication of TRS.

• Despite the efficacy of clozapine, one-third of TRS patients may not respond fully to this drug, and therefore add-on strategies have been suggested in selected cases of clozapine failure; an example of this strategy with new compounds is the add-on of cariprazine, especially in those patients with predominantly negative symptoms. In this direction, more studies are warranted.

• Recently, a few new options of antipsychotic molecules with a novel mechanism of action licensed for schizophrenia treatment or in an advanced stage of clinical trial development have emerged: lumateperone (a multi-acting drug including a glutamate neurotransmission modulation), xanomeline + trospium combination (acting mainly as M1-M4 central muscarinic agonist), SEP-363856 (a TAAR1 agonist) are, among others, the most interesting ones.

• Despite that the indication of these molecules is not, currently, the TRS neurobiological basis are of interest, especially in those cases of TRS whose onset appears after a period of successful antipsychotics’ response and at least theoretically can be ascribed to or increased dopamine DR2 B^max or D2R^High affinity increase possibly leading to supersensitivity psychosis.

• Other antipsychotics (i.e. amisulpride, aripiprazole) as an augmentation to clozapine have been suggested, and novel strategies potentially implicating directly on a glutamatergic approach should be considered, such as benzoate and D-amino acids add-on to clozapine. However, more studies are needed before drawing a firm conclusion.

This box summarizes key points contained in the article.

Abbreviations

TRS: Treatment Resistant Schizophrenia

Non-TRS: non-Treatment Resistant Schizophrenia

TRRIP: Treatment Response and Resistance in Psychosis

FEP: First-Episode Psychosis

SSP: Supersensitivity Psychosis

PANSS: Positive and Negative Syndrome Scale

UTRS: Ultra Treatment Resistant Schizophrenia

GABA: γ-Aminobutyric acid

HC: Healthy Control

GAF: Global Assessment of Functioning

H-MRS: Proton Magnetic Resonance Spectroscopy

ACC: Anterior Cingulate Cortex

PSD: Post Synaptic Density

D2R: Dopamine D2 receptor

D1R: Dopamine D1 receptor

D3R: Dopamine D3 receptor

AEs: Adverse effects

5-HT_1AR: 5-hydroxytryptamine type 1A receptor

5-HT_2AR: 5-hydroxytryptamine type 2A receptor

5-HT_2BR: 5-hydroxytryptamine type 2B receptor

5-HT_2CR: 5-hydroxytryptamine type 2C receptor

5-HT₃R: 5-hydroxytryptamine type 3 receptor

5-HT₆R: 5-hydroxytryptamine type 6 receptor

PET: Positron Emission Tomography

18F-DOPA: [18F]-L-dihydroxyphenylalanine

BPRS: Brief Psychiatric Rating Scale

SAPS: Scale for the Assessment of Positive Symptoms

SANS: Scale for the Assessment of Negative Symptoms

CGI-S: Global Clinical Impression-Severity of Illness

CGI-SCH-S: Clinical Global Impression of Schizophrenia Scale-Severity;

CGI-SCH-I: Clinical Global Impression of Schizophrenia Scale-Improvement

POMS: Profile of Mood States

RCT: Randomized Clinical Trial

LAI: Long Acting Injectable

PSP: Social Performance Scale

NMDAR: N-methyl-D-aspartate receptor

DAAOI: D-amino acid oxidase inhibitor

DAAO: D-amino acid oxidase

QOLS: Quality of Life Scale

M1: Muscarinic receptor 1

M4: muscarinic receptor 4

BBB: Blood–Brain Barrier

GSK-3β: Glycogen Synthase Kinase-3β

EPS: Extrapyramidal symptoms

GlyT1: Glycine transporter type-1

FDA: Food and Drug Administration

fMRI: functional Magnetic Resonance Imaging

TAAR1: Trace amine-associated receptor 1

Bcl-2: B-cell leukemia/lymphoma 2 protein

PARP: Poly(ADP-ribose) polymerase

AMPAR: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor

COMT: Catechol-O-methyltransferase

cAMP: Cyclic adenosine monophosphate

PKA: Protein kinase A

DAT: Dopamine transporter

P: phosphorization

SOFAS: Social and Occupational Functioning Assessment Scale

BID: bis in die

TEAEs: Treatment-emergent adverse events

ECG: Electrocardiogram

AIMS: Abnormal Involuntary Movement Scale

BARS: Barnes Akathisia Rating Scale

SAS: Simpson-Angus extrapyramidal side effects

C-SSRS: Columbia-Suicide Severity Rating Scale

MATRICS: Measurement and Treatment Research to Improve Cognition in Schizophrenia

SQLS: Schizophrenia Quality of Life Scale

HDRS: Hamilton Depression Rating Scale

CGAS: Children’s Global Assessment Scale

CDRS-R: Children’s Depression Rating Scale-Revised

NSA-16: Negative Symptom Assessment-16

ER: extended release

C_max: Maximum Plasma Concentration

AUC: Area Under the Curve

NAC: N-acetylcysteine

Declaration of interest

A de Bartolomeis has received: research funding from AstraZeneca, Janssen-Cilag, Bristol-Myers Squibb, Otsuka, Sanofi, and Lundbeck; honoraria for advisory board activity from Janssen-Cilag Italy, Eli Lilly, Bristol-Myers Squibb, Tedeka, Recordati, Mylan, Trivia, Chiesi, Otsuka, Lundbeck; and honoraria as a speaker at non-educational activities sponsored by AstraZeneca Italia, Janssen-Cilag Italy, Eli Lilly, Bristol-Myers Squibb, Tedeka, Recordati. A de Bartolomeis, F Iasevoli, and M Fornaro are full-time employees at the University of Naples ‘Federico II.’ M Ciccarelli and A Barone are PhD candidates at the Department of Neuroscience, University of Naples ‘Federico II.’ L Vellucci is enrolled in the Residency Program of Psychiatry at University of Naples ‘Federico II.’ The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/14656566.2022.2145884

Additional information

Funding

This paper was not funded.