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.
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 Bmax or D2RHigh 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-HT1AR: 5-hydroxytryptamine type 1A receptor
5-HT2AR: 5-hydroxytryptamine type 2A receptor
5-HT2BR: 5-hydroxytryptamine type 2B receptor
5-HT2CR: 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
Cmax: 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