Clozapine’s multiple cellular mechanisms: What do we know after more than fifty years? A systematic review and critical assessment of translational mechanisms relevant for innovative strategies in treatment-resistant schizophrenia

Bartolomeis, Andrea de; Vellucci, Licia; Barone, Annarita; Manchia, Mirko; Luca, Vincenzo De; Iasevoli, Felice; Correll, Christoph U.

doi:10.1016/j.pharmthera.2022.108236

Cited by 32 publications

(31 citation statements)

References 710 publications

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“…Most antipsychotics, albeit with individual differences, share the common feature of occupying the dopamine D2 receptor (D2R), which is considered the main mechanism responsible for their therapeutic effect [ 3 ]. Despite the relevance of dopamine-related action, atypical antipsychotics and novel compounds in experimental trials modulate other neurotransmitter pathways, including the serotonergic, glutamatergic, and adrenergic ones with a putative beneficial effect on psychotic symptoms [ 4 , 5 , 6 ]. Mounting evidence suggests that antipsychotics can lead to morphological and synaptic changes in the brain through the modulation of processes that regulate synaptic plasticity, dendritic spine architecture, and postsynaptic density [ 5 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

“…Despite the relevance of dopamine-related action, atypical antipsychotics and novel compounds in experimental trials modulate other neurotransmitter pathways, including the serotonergic, glutamatergic, and adrenergic ones with a putative beneficial effect on psychotic symptoms [ 4 , 5 , 6 ]. Mounting evidence suggests that antipsychotics can lead to morphological and synaptic changes in the brain through the modulation of processes that regulate synaptic plasticity, dendritic spine architecture, and postsynaptic density [ 5 , 7 ]. In addition, antipsychotics may promote a functional reorganization of neural connections and modify the correlation pattern existing between pairs of brain regions [ 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

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Antipsychotics-Induced Changes in Synaptic Architecture and Functional Connectivity: Translational Implications for Treatment Response and Resistance

Bartolomeis¹,

Simone²,

Ciccarelli³

et al. 2022

Biomedicines

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Schizophrenia is a severe mental illness characterized by alterations in processes that regulate both synaptic plasticity and functional connectivity between brain regions. Antipsychotics are the cornerstone of schizophrenia pharmacological treatment and, beyond occupying dopamine D2 receptors, can affect multiple molecular targets, pre- and postsynaptic sites, as well as intracellular effectors. Multiple lines of evidence point to the involvement of antipsychotics in sculpting synaptic architecture and remodeling the neuronal functional unit. Furthermore, there is an increasing awareness that antipsychotics with different receptor profiles could yield different interregional patterns of co-activation. In the present systematic review, we explored the fundamental changes that occur under antipsychotics’ administration, the molecular underpinning, and the consequences in both acute and chronic paradigms. In addition, we investigated the relationship between synaptic plasticity and functional connectivity and systematized evidence on different topographical patterns of activation induced by typical and atypical antipsychotics.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Antipsychotics-Induced Changes in Synaptic Architecture and Functional Connectivity: Translational Implications for Treatment Response and Resistance

Bartolomeis¹,

Simone²,

Ciccarelli³

et al. 2022

Biomedicines

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“…The decrease in alpha power may be a biomarker that translates clinically, as a recent phase 3 clinical trial showed that a centrally acting muscarinic receptor agonist effectively treats schizophrenia . Also, clinical studies consistently show that single-dose administration of the prototypical, second-generation antipsychotic, clozapine, which has unique and relatively low activity at dopamine D 2 receptors, reduces alpha power; clozapine also suppresses MK-801-elicited increases in alpha power . Other FDA-approved neuropsychiatric medications, including the new antidepressant allopregnanolone, which acts as a GABA A positive allosteric modulator, decrease alpha power and increase beta power, as we observed with FPT .…”

Section: Discussionmentioning

confidence: 99%

FPT, a 2-Aminotetralin, Is a Potent Serotonin 5-HT_1A, 5-HT_1B, and 5-HT_1D Receptor Agonist That Modulates Cortical Electroencephalogram Activity in Adult Fmr1 Knockout Mice

Saraf

McGlynn

Bhatavdekar

et al. 2022

ACS Chem. Neurosci.

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There are no approved medicines for fragile X syndrome (FXS), a monogenic, neurodevelopmental disorder. Electroencephalogram (EEG) studies show alterations in restingstate cortical EEG spectra, such as increased gamma-band power, in patients with FXS that are also observed in Fmr1 knockout models of FXS, offering putative biomarkers for drug discovery. Genes encoding serotonin receptors (5-HTRs), including 5-HT 1A , 5-HT 1B , and 5-HT 1D Rs, are differentially expressed in FXS, providing a rationale for investigating them as pharmacotherapeutic targets. Previously we reported pharmacological activity and preclinical neurotherapeutic effects in Fmr1 knockout mice of an orally active 2-aminotetralin, (S)-5-(2′-fluorophenyl)-N,Ndimethyl-1,2,3,4-tetrahydronaphthalen-2-amine (FPT). FPT is a potent (low nM), high-efficacy partial agonist at 5-HT 1A Rs and a potent, low-efficacy partial agonist at 5-HT 7 Rs. Here we report new observations that FPT also has potent and efficacious agonist activity at human 5-HT 1B and 5-HT 1D Rs. FPT's K i values at 5-HT 1B and 5-HT 1D Rs were <5 nM, but it had nil activity (>10 μM K i ) at 5-HT 1F Rs. We tested the effects of FPT (5.6 mg/kg, subcutaneous) on EEG recorded above the somatosensory and auditory cortices in freely moving, adult Fmr1 knockout and control mice. Consistent with previous reports, we observed significantly increased relative gamma power in untreated or vehicle-treated male and female Fmr1 knockout mice from recordings above the left somatosensory cortex (LSSC). In addition, we observed sex effects on EEG power. FPT did not eliminate the genotype difference in relative gamma power from the LSSC. FPT, however, robustly decreased relative alpha power in the LSSC and auditory cortex, with more pronounced effects in Fmr1 KO mice. Similarly, FPT decreased relative alpha power in the right SSC but only in Fmr1 knockout mice. FPT also increased relative delta power, with more pronounced effects in Fmr1 KO mice and caused small but significant increases in relative beta power. Distinct impacts of FPT on cortical EEG were like effects caused by certain FDA-approved psychotropic medications (including baclofen, allopregnanolone, and clozapine). These results advance the understanding of FPT's pharmacological and neurophysiological effects.

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“…The reason for the superiority of clozapine over other AP still remains unknown but several hypotheses exist, such as clozapine's affinity for the serotonin receptor (5-HT2R), for the dopamine 1 receptor (D1R), for the adrenoreceptor (α2c), and for muscarinic receptors (M1-M4). 74 In addition, there is evidence that many DD patients refuse AP treatment, chiefly because they do not consider themselves 'psychotic,' but also because they cannot tolerate the side effects. 73 Brownstone et al 75 have provided some tips on how best to address the issue of AP refusal in the context of delusional parasitosis, sometimes referred to as delusional infestation (DI).…”

Section: What Can Be Done For Treatment Resistance or Antipsychotic R...mentioning

confidence: 99%

“…Try clozapine. Try LAIs 74. Prevention delusional disorder J Explor Res Pharmacol authors recommended a multidisciplinary approach, a rapid response to referrals, and flexibility with regard to assessment times and settings (e.g.…”

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confidence: 99%

Primary and Secondary Prevention in Delusional Disorder

González-Rodríguez¹,

Seeman²

2022

J Explor Res Pharmacol

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Background and objectives: Delusional disorder (DD), once entrenched, responds poorly to currently available treatment. This calls for community and individual preventive measures. Our goal was to conduct a literature review exploring the possibilities of prevention.Methods: This is a narrative review based on the PubMed database from inception until July 2022. Search terms were "delusional disorder" OR "delusional psychosis", AND "prevention," OR "early detection," OR "early treatment." Results:We found very little literature specific to DD, but considerable evidence for primary and secondary preventive strategies in use for delusional psychosis (a psychotic illness with prominent delusions). Community strategies included addressing socioeconomic disadvantage and mental health stigma, improving mental health service accessibility, screening for and treating potential precursors to DD, such as sensory and cognitive deficits, as well as psychiatric. symptoms such as depression, anxiety, sleep disturbance, and substance abuse. Secondary community prevention relied on early detection programs and specialized services for early treatment of DD symptoms and their co-morbidities. Individual forms of secondary prevention were interventions especially geared toward illness denial, treatment nonresponse and antipsychotic (AP) refusal. Effective secondary prevention reduced symptom intensity and diminished the risk for fatal outcomes such as suicide.Conclusions: Based mostly on the evidence from related disorders, preventive and early treatment strategies, when put into

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Clozapine’s multiple cellular mechanisms: What do we know after more than fifty years? A systematic review and critical assessment of translational mechanisms relevant for innovative strategies in treatment-resistant schizophrenia

Cited by 32 publications

References 710 publications

Antipsychotics-Induced Changes in Synaptic Architecture and Functional Connectivity: Translational Implications for Treatment Response and Resistance

Antipsychotics-Induced Changes in Synaptic Architecture and Functional Connectivity: Translational Implications for Treatment Response and Resistance

FPT, a 2-Aminotetralin, Is a Potent Serotonin 5-HT_1A, 5-HT_1B, and 5-HT_1D Receptor Agonist That Modulates Cortical Electroencephalogram Activity in Adult Fmr1 Knockout Mice

Primary and Secondary Prevention in Delusional Disorder

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Clozapine’s multiple cellular mechanisms: What do we know after more than fifty years? A systematic review and critical assessment of translational mechanisms relevant for innovative strategies in treatment-resistant schizophrenia

Cited by 32 publications

References 710 publications

Antipsychotics-Induced Changes in Synaptic Architecture and Functional Connectivity: Translational Implications for Treatment Response and Resistance

Antipsychotics-Induced Changes in Synaptic Architecture and Functional Connectivity: Translational Implications for Treatment Response and Resistance

FPT, a 2-Aminotetralin, Is a Potent Serotonin 5-HT1A, 5-HT1B, and 5-HT1D Receptor Agonist That Modulates Cortical Electroencephalogram Activity in Adult Fmr1 Knockout Mice

Primary and Secondary Prevention in Delusional Disorder

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Product

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About

FPT, a 2-Aminotetralin, Is a Potent Serotonin 5-HT_1A, 5-HT_1B, and 5-HT_1D Receptor Agonist That Modulates Cortical Electroencephalogram Activity in Adult Fmr1 Knockout Mice