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Antipsychotics: Predicting Response/Maximizing Efficacy
Published in Mark S. Gold, R. Bruce Lydiard, John S. Carman, Advances in Psychopharmacology: Predicting and Improving Treatment Response, 2018
R. Bruce Lydiard, John S. Carman, Mark S. Gold
As was noted above, antipsychotic drugs probably exert their therapeutic effect via DA receptor blockade. In the 1960s Connell15 and others16 observed that amphetamine, a drug with potent DA-releasing properties, could cause psychotic symptoms in normal individuals. The symptoms — thought disorder, auditory hallucinations, and paranoid delusions — were remarkably similar to those observed in schizophrenic illness. Furthermore, these symptoms were quickly abolished by antipsychotic medication.17 These observations collectively contributed to the “dopamine hypothesis” of schizophrenia.9 Simply stated, the hypothesis postulates that excessive DA activity underlies schizophrenic illness. It is supported by indirect pharmacologic evidence that agents which cause an increase in dopaminergic activity (i.e., amphetamine, methylphenidate, l-dopa) induce an exacerbation of schizophrenic symptoms, and drugs causing a reduction of dopaminergic activity (i.e., DA receptors blockers, DA release, or synthesis inhibitors) result in a diminution of schizophrenic symptoms. There is considerable evidence to indicate that the DA hypothesis has significant merit as a model for studying psychotic states. However, as with any simplified theory, there are many problems with the DA hypothesis for schizophrenia. It is known, for example, that some schizophrenic patients are quite resistant to the expected worsening after administration of d-amphetamine.18,19 Some investigators have even shown an improvement in psychosis after amphetamine19 or l-dopa20,21 was given to schizophrenic patients. Additionally, some schizophrenic patients either do not respond to antipsychotic medication22 or become worse23 after drug treatment. There are no truly antischizophrenic drugs, i.e., no cures for schizophrenia. There are treatments (i.e., antipsychotic drugs) for certain symptoms of psychosis which often accompany schizophrenic and other psychoses. While the final common pathway in many schizophrenic and other psychotic illnesses may be an overactive DA system in the brain, there are probably many ways to arrive at that neurochemical state. Numerous etiologies for schizophrenia have been proposed, and include alterations in the function of amine neurotransmitters (DA, norepinephrine, serotonin), CNS peptides (endorphins and others), viral infections, autoimmune disease, production of endogenous psychotogens, and others.9 Over 40 postulated neurotransmitters and neuromodulators coexist in the CNS and interact in a complex and poorly understood fashion. Schizophrenia is probably a variety of illnesses, which respond symptomatically to antidopaminergic agents much of the time. New research may provide “cures”, but for now we are limited to the clinical use of DA receptor blocks with which to treat the spectrum of illnesses called schizophrenia.
An evaluation of lumateperone tosylate for the treatment of schizophrenia
Published in Expert Opinion on Pharmacotherapy, 2020
Pankhuri Vyas, Brian Jaeho Hwang, James Robert Brašić
The dopamine hypothesis of schizophrenia proposed that positive symptoms of schizophrenia result from dysfunction of dopaminergic neurotransmission [6]. In the resting tonic state, people with schizophrenia may exhibit lower extracellular dopamine than healthy individuals; in the excited phasic state, people with schizophrenia may experience higher intrasynaptic dopamine levels than healthy individuals [7]. The excessive intrasynaptic dopamine may be associated with the positive symptoms of schizophrenia.
A diffusion weighted imaging study of basal ganglia in schizophrenia
Published in International Journal of Psychiatry in Clinical Practice, 2018
Giuseppe Delvecchio, Alessandro Pigoni, Cinzia Perlini, Marco Barillari, Amelia Versace, Mirella Ruggeri, A. Carlo Altamura, Marcella Bellani, Paolo Brambilla
Since the introduction of structural magnetic resonance imaging (MRI), numerous neuroimaging studies provided evidence of selective brain abnormalities in several cortical and subcortical structures in schizophrenia (Zampieri et al. 2014; van Erp et al. 2014, 2016; Zhang et al. 2015; Yue et al. 2016). Among these structures, the basal ganglia deserve particular attention, being subcortical nuclei rich in dopaminergic neurons (Cazorla et al. 2014). They are composed by the caudate nucleus, the lenticular nucleus (which comprises the putamen and the globus pallidus), the subthalamic nucleus and the substantia nigra. The housing of dopaminergic neurons in these structures explained their involvement in the neuropathology of schizophrenia, a well-established dopaminergic disorder (Brisch et al. 2014). Indeed, the classical ‘dopamine hypothesis’ of schizophrenia proposed that hyperactivity of dopamine transmission might be responsible for symptoms in psychosis and schizophrenia (Howes and Kapur 2009). In particular, by inhibiting the dopaminergic signaling of D2-receptors, which are highly concentrated in the basal ganglia, the antipsychotic drugs seem to reduce positive psychotic symptoms in patients affected by schizophrenia and therefore they have been considered the preferential treatment of this disorder (Dunlop and Brandon 2015). Furthermore, basal ganglia seem to be associated not only with the clinical manifestation of the disease but also they might be involved in different cognitive functions commonly impaired in schizophrenia, as they are part of the cortico-striato-thalamocortical circuits, which are central for information processing and attention (Arsalidou et al. 2013). Indeed, although the primary role of basal ganglia has been reported to be the fine regulation of complex movements (Tremblay et al. 2015), recent studies now supported their implication in cognitive functions, including attention, working memory, reward and executive functions (Arsalidou et al. 2013; Rabinovici et al. 2015; Vatansever et al. 2016). This evidence has been also supported by a rodent model of schizophrenia which reported that an imbalance between cortical and subcortical dopamine resulted in severe cognitive deficits (Eyles et al. 2012).