January 10th, 2018
Pharmacotherapeutic treatment for schizophrenia – classification of drugs and mechanism of action
Classification of drugs used for treatment of schizophrenia
Drugs used to for treatment of schizophrenia fall under different classes. Initial treatment for schizophrenia was advanced through dopamine receptor antagonists, which have come to be referred to as antipsychotic drugs (Meltzer 2002). Such typical (first generation) antipsychotics include drugs such as Chlorpromazine, haloperidol, thioridazine, molindone, pimozide and thioridazine (Metzer 2002). Such drugs are also referred to as neuroleptics because they are implicated in catalepsy (muscular rigidity) in experimental animals and extrapyramidal side effects (EPSs; movement disorders such as tremor and akathisia – sensation of inner restlessness that entrenches the urge to keep moving, and dystonia) in humans (Metzer 2002). These adverse side effects of typical antipsychotics led to the development of second generation (atypical) antipsychotics in the 1990s (Metzer 2002).
The designation of second-generation antipsychotics as atypical antipsychotics arose from observations that clozapine achieved antipsychotic effects without EPSs (Metzer 2002). Subsequently, atypical antipsychotics have included other compounds with similar, low EPS-characteristic, though clinical investigators have contested such a broad description (Metzer 2002). Apart from clozapine, other atypical antipsychotics include risperidone, quetiapine, ziprasidone, olanzapine, sertindole and iloperidone; iloperidone was approved for schizophrenia treatment in 2009 (Metzer 2002; Johnsen et al. 2010; Weiden 2012). Schizophrenia drugs could also be classified according to the receptors they target. In this respect the drugs could be dopaminergic (target dopamine receptors), serotonergic (have affinity for serotonin receptors) and glutamatergic (targeting glutamate receptors). Drugs such as clozapine show affinity for the three types of receptors (Metzer 2002; Tiihonen & Wahlbeck 2012).
Mechanisms of action
Antipsychotic agents are thought to work through their blockade of various receptors that function in the central nervous system. The first of these receptors are the dopamine receptors. Dopamine receptors were implicated in schizophrenia treatment by the dopamine hypothesis of schizophrenia. Formulated by Rossum in 1967, the hypothesis attributes the development of schizophrenia and other psychoses to increased secretion and transmission of dopamine in dopaminergic neurons (Lindenmayer et al. 2007; Metzer 2002, Farde 1997). Subsequently, most antipsychotics have been shown to have a high affinity for D2 – dopamine receptors; their binding to such receptors is thus postulated to hinder dopaminergic neurotransmission (Metzer 2002, Lindenmayer et al. 2007). Such activity is initiated in the D2 –receptors in the mesolimbic nuclei (e.g. stria terminalis and amygdala) with blockade of D2 – receptors in the terminal regions such as nucleus accumbens having an initial effect of increased dopaminergic activity in the substantia nigra and ventral tegmentum (Metzer 2002). Subsequently, activity of DA neurons declines gradually and ultimately resulting into complete inactivation of DA neurons firing in both the mesolimbic nuclei and terminal regions (Metzer 2002).
In addition to the D2-receptor blockade, atypical antipsychotics also have a high affinity for 5-HT2A receptors (Breier 1995; Metzer 2002; Lindenmayer et al. 2007; Weiden 2012). Such higher affinity for 5-HT2A than D2 receptors is thought to regulate the dopamine transmission systems in the limbic and nigrostriatal regions, thus reducing the adverse effects (e.g. EPSs) associated with extensive blockade of dopamine transmission (Iqbal & van Praag 1995; Metzer 2002; Lindenmayer et al. 2007; Zhou et al. 2006). Apart from 5-HT2A receptor, other serotonin receptors suggested to play some role in the regulation of the dopamine neurotransmitter systems include 5-HT1A, 5-HT2C, 5-HT3, 5-HT6, and 5-HT7 (Metzer 2002; Meltzer et al. 2003). These receptors have been identified following their binding by different antipsychotics (Iqbal & van Praag 1995, Metzer 2002; Meltzer et al. 2003, Davies, Conley & Puskar 2010). Other receptors thought to play a role in treatment of schizophrenia are glutamate receptors whose blockade is suggested to regulate dopaminergic neurotransmission (Tiihonen & Wahlbeck 2012).
Neurotransmitter receptors (e.g. D2 and 5HT2A) are G protein-coupled receptors, which consist of seven transmembrane domains, and functions via a second-messenger system (Davies, Conley & Puskar 2010). Examples of second messengers operating in the nervous system are cyclic AMP (cAMP; for D1, D2, 5-HT1A, 5-HT1B and 5-HT2 receptors), and phospholipase C and Inositol triphosphate (IP3) – for glutamate, and 5-HT1B (Lehninger, Nelson & Cox 2005, pp. 435 – 445). Whenever a ligand (e.g. dopamine, serotonin and glutamate) binds to the respective receptor, the activated receptor stimulates the attached G protein to exchange the bound GDP with GTP (Lehninger, Nelson & Cox 2005, pp. 435 – 445). The resultant GTP-protein dissociates from the activated receptor and binds an adjacent enzyme (e.g. adenylyl cyclase), which catalyses the activation of a second messenger (e.g. cAMP) (Lehninger, Nelson & Cox 2005, p. 435). The activated second messenger participates in a cascade of reactions, regulating the activity of enzymes operating in multiple processes. Relevant to the antipsychotic activity are processes such as synthesis and release of neurotransmitters (such as dopamine and catecholamines), and regulation of intracellular calcium concentration, which determines membrane potential hence transmission of messages across neurons (Lehninger, Nelson & Cox 2005, p. 440). Accordingly, blockade of dopamine receptors by antipsychotics averts such a cascade, with the antipsychotics’ binding of 5-HT and glutamate receptors regulating the extent of such blockade, thus reducing the adverse effects associated with D2-receptor blockade. Go to part 3.