Antipsychotic Drugs
Since the antipsychotic action of chlorpromazine was first demonstrated 60 years ago by Delay et al.,[34] antipsychotic drugs have represented a cornerstone in the treatment of schizophrenia and related disorders.[35] The drugs principally target positive symptoms of psychosis, such as auditory hallucinations and delusions and to a much lesser degree other dimensions of psychosis such as negative, cognitive and affective dysfunctions.[36,37] Antipsychotic agents have, in a recent meta-analysis based on randomized, controlled trials, been found to have moderate effect sizes in treating overall psychotic symptoms.[36] However, large individual differences exist with regards to both effects and burden of side effects. Based on current evidence, it is not possible to predict in advance which antipsychotic agent will be optimal for the individual patient,[38] leaving treatment to a trial-and-error experience.
During the years following the launch of chlorpromazine, a number of new agents were developed by the pharmaceutical industry that shared the same antipsychotic effects but had differing chemical properties, see Shen[39] for details. It took a decade from the early introduction of antipsychotic medication to the discovery that the action was antagonism of the dopaminergic system as the biological substrate of the antipsychotic effects.[40] Accumulating molecular imaging evidence confirms schizophrenia is associated with an altered dopaminergic neurotransmission. Specifically, schizophrenia seems associated with a 14% increase in the striatal presynaptic dopaminergic synthesis capacity, as revealed by 18F/11C-DOPA PET studies in patients versus controls (for updated meta-analyses, see [27,41]). Disturbed dopaminergic function, with presynaptic striatal hyperdopaminergia, is the most replicated neurochemical finding in psychosis, and all antipsychotic drugs antagonize dopaminergic transmission at the dopaminergic type 2 (D2) receptors in the CNS.[42] The hyperdopaminergic state is particularly relevant with regards to the positive symptoms of psychosis, such as delusions and hallucinations.[42] In line with the above findings in HR subjects, subcortical alterations in striatal dopamine are already evident before the onset of psychosis and can predate the development of frank illness.[43]
The details of the link between dopaminergic antagonism and the observed antipsychotic phenomenological effects of the drugs are however still not known, which is contributing to the trial-and-error effects with regard to individual patients and individual variability. Dopamine has been implicated in motivation and reward systems in the brain and in the process of attribution of salience, whereby stimuli awaken ones attention and drive a 'wanting' to respond because of the stimuli's association with reward.[44,45] Kapur and Mamo[46] hypothesized that in the physiologic situation, a stimulus leads to dopamine release, which mediates motivational salience: a reward-associated stimulus grabs the attention of an individual and leads to goal-directed actions. In psychosis, the dopaminergic transmission in the mesolimbic system is dysregulated and stimuli induce inappropriate dopamine release, leading to an abnormal salience of both external and internal stimuli, whereby insignificant events and stimuli grab the attention of the patient. In this context, auditory hallucinations are perceptual phenomena that develop as a result of abnormal salience of inner mental processes such as thoughts, language and memories.[47] Delusions arise secondarily as results of cognitive attempts to internally make sense of the abnormal experiences. According to this hypothesis, antipsychotic drugs execute their effects by the dampening of salience following dopaminergic antagonism. Later versions of the dopamine hypothesis of schizophrenia have emphasized much more complex alterations in the dopaminergic system than mere hyperdopaminergic functioning in the striatum.[42] Furthermore, other drug targets are probably to be involved in the mediation of the effects of antipsychotic drugs, as antipsychotics have affinities for a broad display of receptors in the CNS ( Table 1 ) (see [48] for an overview). For the sake of focus, only those targets considered of relevance to the present review will be commented. In line with this, serotonin receptors have been identified as important targets of the second-generation antipsychotics (SGAs). SGAs are characterized by a relatively strong antagonism effect at the serotonin 5-HT2A receptors and lower potency for dopaminergic antagonism at the D2 receptors as opposed to the first-generation antipsychotics (FGAs). FGAs more selectively target dopamine receptors and are only weak serotonin receptor antagonists.[49,50] The higher 5-HT2A/D2 receptor affinity ratio of the SGAs compared with the FGAs has been hypothesized as a key mechanism behind the lower propensities of the SGAs for causing extrapyramidal side effects. Moreover, many SGAs target also additional subclasses of serotonin receptors which may mediate beneficial neurocognitive effects of the drugs.[49]
The focus of brain research related to psychotic disorders has in recent years shifted from focal pathology to disturbances in connectivity and circuits. The following sections will briefly review the most central potential drug targets in relation to auditory hallucinations.
Lewis and Sweet[51] summarize recent findings regarding some of the main transmitter circuitries proposed to be involved in schizophrenia, emphasizing the interplay between dopaminergic, glutamatergic, and GABAergic neurons. There is, for example, an evidence of reduced excitatory input to cortical layer 3 pyramidal (glutamatergic) neurons in the dorsolateral prefrontal cortex, resulting in reduced excitatory output from these neurons.[51,52] Furthermore, altered neurotransmission is found for a subset of GABAergic interneurons in schizophrenia.[53] Finally, dopaminergic innervation from the mesencephalon, modifying the functions of both pyramidal cells and interneurons, is decreased in schizophrenia.[54] Smaller cell bodies and dendritic trees, as well as fewer axonal terminals on glutamatergic pyramidal cells have been found in several cortical areas in schizophrenia.[51] There is indeed abundant literature implicating the glutamatergic system in schizophrenia, since its earliest phases,[28] more specifically dysfunction of the NMDA receptors.[55] Glutamate is the most widespread excitatory neurotransmitter in the CNS and is implicated in several physiological as well as pathological processes.[56] Excitotoxicity caused by excessive glutamate concentrations leading to increased inflow of Ca2+ through the NMDA receptor ion channel is responsible for the neuronal loss associated with such diverse conditions as ischemic stroke and chronic neurodegenerative disorders including Alzheimer's disease and amyotrohophic lateral sclerosis.[57] While the striatal hyperdopaminergic situation principally accounts for the positive symptoms of psychosis, antagonism at the glutamatergic NMDA receptors may induce also negative symptoms and cognitive dysfunctions resembling those seen in schizophrenia.[55] Theoretically, increasing the NMDA receptor transmission should accordingly be beneficial in schizophrenia but available glutamatergic agents targeting the NMDA receptor have thus far not proven to be effective in the treatment of schizophrenia.[58] The evidence does suggest, however, an effect against positive symptoms of adjunctive glycine, a modulator and coagonist at the NMDA receptor.[58] Moreover, preclinical studies point towards potential therapeutic effects of glutamatergic metabotropic receptor modulators but the effects remain to be confirmed in clinical trials.[58] An untested possibility is also that glutamatergic hyperactivity may be directly or indirectly involved in the elicitation of auditory hallucinations, and that these are not cognitively inhibited owing to GABAergic hypoactivity. Measures of certain transmitter concentrations or levels in specific brain regions, example glutamate and GABA, are now possible through MR spectroscopy, and such measures can then be correlated with blood oxygen level-dependant (BOLD) fMRI activations in the same and nearby regions.[59,60] The SGAs clozapine and olanzapine are also partial agonists for several subtypes of cholinergic muscarinic receptors.[58] Alterations of the cholinergic system has since a very long time been implicated in the pathophysiology of schizophrenia.[61] Of particular interest to the present review is that cigarette smoking has been found to transiently normalize auditory sensory gating in patients with schizophrenia.[62] Moreover, nicotine-containing gum has been found to normalize the same deficit in nonsmoking relatives with abnormal sensory gating of patients with schizophrenia.[63] The cholinergic system may be particularly central in the patho-etiologies of psychosis in Alzheimer's and Parkinson's disease, respectively.[64,65]
Some of the latest insights into brain functions involved in schizophrenia that could also represent drug targets stem from studies on myelin. On the structural level, recent systematic reviews conclude that antipsychotic drugs are associated with changes in both gray matter and myelin.[12,66] The myelin hypothesis of schizophrenia was first presented in 2001 after the finding of dysregulation of myelin-associated genes in schizophrenia.[67] Later compelling evidence of disturbed functioning of oligodendrocytes and myelin has been put forward from both imaging and genetic studies.[68,69] The dysfunctions seem to be primary features. Abnormalities could cause decreased conduction velocities and synaptic instability, as well as less axonal sprouting, possibly leading to altered information processing of relevance to psychosis and cognitive dysfunction. Of relevance is the fact that demyelinisation in different preclinical experimental models has been found to increase dopaminergic transmission, therefore linking myelin dysfunctions to hyperdopaminergia although the mechanisms involved remain essentially unknown, see Takahashi et al.[69] for an example of a more detailed review of the interplay between myelin and dopamine and glutamate. In relation to myelin as a drug target of antipsychotics, Garver et al.,[70] using a magnetic resonance diffusion tensor imaging technique, found impaired myelin integrity during acute psychosis with restoration in drug responding patients. Furthermore, recent preclinical studies have demonstrated myelin-protecting and remyelinisational properties of at least some antipsychotic drugs.[71–73] Hugdahl et al.[2] propose, based on fMRI findings, that auditory hallucinations in part may be caused by dysfunctional fronto-parietal executive cortical networks, resulting in inadequate suppression of the uncontrolled firing in speech areas of the left temporal lobe. Theoretically, impaired myelin could contribute to the dysfunctions of the networks and to increased dopamine.[74]
Expert Rev Neurother. 2013;13(1):23-36. © 2013 Expert Reviews Ltd.
