Non-dopaminergic Neurotransmitter Systems Research Articles

Relationship between 123I-FP-CIT-SPECT and gait impairments in drug-naïve individuals with Parkinson's disease

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by loss of nigrostriatal dopaminergic neurons [1]. In addition to cardinal motor symptoms, individuals with PD suffer of gait impairment [2]. Although functional imaging is useful for the diagnosis and pathophysiological evaluation of PD, little is known about the relationship between neuroimaging findings and PD clinical features. A study found a correlation between dopamine denervation and impaired gait automaticity [3]; others reported no association between dopaminergic denervation and some gait parameters, such as stride length and velocity [4,5], assuming that deficits in nondopaminergic neurotransmitter systems played the main role in gait impairments [3]. We aimed to examine the relationship between striatal dopaminergic depletion with disease severity in motor symptoms and gait variables in drug-naïve individuals with PD, in order to find where nigrostriatal pathway mainly acts. A total of 18 drug-naïve individuals with PD (mean age 70.4 ± 7.4 yrs) were enrolled. Motor symptoms were evaluated using the modified Hoehn and Yahr (H&Y) stage. Seven spatiotemporal variables of gait were acquired using a GAITRite® electronic walkway under comfortable walking, of which the coefficient of variation and the asymmetry were then calculated. The extent of striatal dopaminergic depletion was evaluated by dopamine transporter imaging with single-photon emission computed tomography using 123I-FP-CIT. Correlations between H&Y stage and gait variables with the specific binding ratios (SBRs) of the striatum (separated into putamen and caudate nucleus) were assessed with the Spearman's correlation coefficients (r). The mean SBRs of both the putamen and the caudate nucleus were significantly associated with the modified H&Y stage, with correlation coefficient of at least 0.60. A moderate correlation was found also between the asymmetry in the SBR of the putamen and the H&Y stage. Moreover, among the spatiotemporal gait variables, a moderate correlation was found between the mean double support duration and its asymmetry with the mean SBRs of both the putamen and the caudate nucleus (Table 1). On the contrary, stride length and velocity showed a weak correlation (below 0.30). Our findings suggest that both disease severity and gait impairments in early PD are associated with decreased dopamine binding in the striatum. Since the double support time showed a moderate correlation with dopaminergic depletion in particular in caudate nucleus, we propose this variable as a marker of the effect of nigrostriatal denervation on gait in individuals with early PD. On the other hand, the poor correlations found between the reduction of stride length and velocity with the nigrostriatal depletion confirmed the hypothesis of a major involvement of other systems (such as the cholinergic) in the control of these variables. Our findings supported the notion that a large part of gait impairments in PD resulted from multisystem degeneration [6,7].

Commentary: Clinical Correlates of Raphe Serotonergic Dysfunction in Early Parkinson's Disease.

Growing and clinical evidence supports the conclusion that Parkinson’s Disease (PD) is a complex multisystem disorder not exclusively affecting the dopaminergic circuits. In fact, the dopaminergic neuronal loss does not cover all the clinical aspects of PD. Therefore, different non-dopaminergic neurotransmitter systems have been invoked as playing a role in the PD clinical picture. Principally, the inefficiency of serotonergic circuitry has been demonstrated in PD animal models, as well as in post-mortem and in vivo human studies. In the recent article published in Brain, Zahi Qamhawi and colleagues interrogated 123I-FP-CIT single-photon emission computed tomography documenting raphe serotonergic dysfunction in a large group of early PD patients compared to a subset of possible PD patients without evidence of dopaminergic deficit (SWEDD) and a population of healthy controls (1). This paper combined an accurate clinical evaluation with a sophisticated neuroimaging protocol and documented in PD patients a mean raphe serotonin (5-HT) transporter availability significantly lower than both SWEDD patients and controls. These findings, achieved in a large cohort of PD patients, enforced previous autoptic examinations documenting serotonergic neurons loss due to Lewy body pathology in the raphe nuclei of PD patients (2). Accordingly, neuroimaging studies have shown the progressive 5-HT transporter availability reduction in the raphe nuclei as PD pathology progresses (3–5). It is well accepted that concentration of 5-HT and its metabolite 5-hydroxyindolacetic acid (5-HIAA) in CSF reflects the serotonergic metabolism and turnover in the CNS (6, 7). We performed a case-control study investigating CSF levels of 5-HT and 5-HIAA in a cohort of PD patients, after a 3-day dopaminergic therapy withdrawal and in absence of serotonergic agents (8). We demonstrated the significant reduction of CSF 5-HT and 5-HIAA concentrations in PD patients compared to controls. We also found the significant reduction of CSF 5-HT and 5-HIAA in the PD population with respect to Alzheimer’s Disease patients (8), thus highlighting that the impairment of serotonergic system could represent a specific effect of synuclein-mediated neurodegeneration (8). As a matter of fact, novel experimental studies in alpha-synuclein (α-syn) mouse model of PD showed the impairment of serotonergic system owing to the intracellular accumulation of α-syn in serotonergic neurons coupled with the reduction of 5-HT levels in lower brainstem (9). Based on the clinical presentation, Qamhawi and collegues divided PD patients into two subgroups corresponding to patients with and without resting tremor. Remarkably, patients with tremor had lower mean raphe 5-HT transporter availability than patients unaffected by tremor. Since tremor amplitude, constancy, and severity negatively correlated with raphe 5-HT transporter availability in the whole PD cohort, authors suggested that the serotonergic system inefficiency could be responsible for parkinsonian tremor. This finding was consistent with previous studies detecting an association between 5-HT receptor availability in the raphe nuclei and severity of parkinsonian tremor (10). However, in our CSF study, we found no differences in CSF 5-HT and 5-HIAA levels between tremor dominant and non-tremor dominant patients. This discrepancy could be ascribed to the fact that Qamhawi and collegues studied de novo early PD patients, whereas we investigated patients with higher Hoehn and Yahr stage and greater motor disability at the Unified PD Rating Scale-motor section. It could be of interest to evaluate in follow-up studies how the serotonergic transmission damage may influence PD motor symptoms along with the progression of the disease. Concurrently, the reliability of the proposed difference in raphe 5-HT transporter availability found by Qamhawi and coworkers in early PD patients should be also analyzed in more advanced PD patients. Remarkably, Qamhawi and coauthors documented that raphe 5-HT transporter availability did not correlate with PD non-motor symptoms, such as fatigue, depression, and sleep-wake cycle disturbances. In agreement with this finding, we did not identify mutual interplays linking CSF 5-HT and 5-HIAA concentrations to depression, apathy, and sleep disturbances. Although our report sustained Qamhawi and coworkers results, literature proposes controversial data regarding the involvement of serotonergic pathways breakage in the pathophysiology of PD non-motor symptoms (11), thus requiring further investigations. All considering, we suppose that the reduced 5-HT transporter availability, as shown by Qamhawi and collegues, and the 5-HT synthesis, metabolism, and turnover impairment, resulting in reduced CSF levels of 5-HT and 5-HIAA (8) may both contribute to the serotonergic transmission dysfunction evident in PD. Hence, serotonin circuitry inefficiency could represent the fitting partner of the dopaminergic deficit in PD.

Neurotransmitter receptor density changes in Pitx3ak mice – A model relevant to Parkinson’s disease

Parkinson’s disease (PD) is the second most common neurodegenerative disorder, characterized by alterations of nigrostriatal dopaminergic neurotransmission. Compared to the wealth of data on the impairment of the dopamine system, relatively limited evidence is available concerning the role of major non-dopaminergic neurotransmitter systems in PD.Therefore, we comprehensively investigated the density and distribution of neurotransmitter receptors for glutamate, GABA, acetylcholine, adrenaline, serotonin, dopamine and adenosine in brains of homozygous aphakia mice being characterized by mutations affecting the Pitx3 gene. This genetic model exhibits crucial hallmarks of PD on the neuropathological, symptomatic and pharmacological level. Quantitative receptor autoradiography was used to characterize 19 different receptor binding sites in eleven brain regions in order to understand receptor changes on a systemic level.We demonstrated striking differential changes of neurotransmitter receptor densities for numerous receptor types and brain regions, respectively. Most prominent, a strong up-regulation of GABA receptors and associated benzodiazepine binding sites in different brain regions and concomitant down-regulations of striatal nicotinic acetylcholine and serotonergic receptor densities were found. Furthermore, the densities of glutamatergic kainate, muscarinic acetylcholine, adrenergic α1 and dopaminergic D2/D3 receptors were differentially altered.These results present novel insights into the expression of neurotransmitter receptors in Pitx3ak mice supporting findings on PD pathology in patients and indicating on the possible underlying mechanisms. The data suggest Pitx3ak mice as an appropriate new model to investigate the role of neurotransmitter receptors in PD. Our study highlights the relevance of non-dopaminergic systems in PD and for the understanding of its molecular pathology.

Pharmacological strategies for the management of levodopa-induced dyskinesia in patients with Parkinson's disease.

L-Dopa-induced dyskinesias (LID) are the most common adverse effects of long-term dopaminergic therapy in Parkinson's disease (PD). However, the exact mechanisms underlying dyskinesia are still unclear. For a long time, nigrostriatal degeneration and pulsatile stimulation of striatal postsynaptic receptors have been highlighted as the key factors for the development of LID. In recent years, PD models have revealed a wide range of non-dopaminergic neurotransmitter systems involved in pre- and postsynaptic changes and thereby contributing to the pathophysiology of LID. In the current review, we focus on therapeutic LID targets, mainly based on agents acting on dopaminergic, glutamatergic, serotoninergic, adrenergic, and cholinergic systems. Despite a large number of clinical trials, currently only amantadine and, to a lesser extent, clozapine are being used as effective strategies in the treatment of LID in clinical settings. Thus, in the second part of the article, we review the placebo-controlled trials on LID treatment in order to disentangle the changing scenario of drug development. Promising results include the extension of L-dopa action without inducing LID of the novel monoamine oxidase B- and glutamate-release inhibitor safinamide; however, this had no obvious effect on existing LID. Others, like the metabotropic glutamate-receptor antagonist AFQ056, showed promising results in some of the studies; however, confirmation is still lacking. Thus, to date, strategies of continuous dopaminergic stimulation seem the most promising to prevent or ameliorate LID. The success of future therapeutic strategies once moderate to severe LID occur will depend on the translation from preclinical experimental models into clinical practice in a bidirectional process.

Central pharmacokinetics of levodopa: Lessons from imaging studies.

Functional imaging may be particularly helpful for the assessment of levodopa (l-dopa) response and long-term complications of therapy in Parkinson's disease. Radiotracer imaging allows the quantitative determination of regional changes in blood flow and glucose metabolism, as well as alterations in brain connectivity and network activation and changes in dopamine receptors, non-dopaminergic neurotransmitter systems, and to a lesser extent, signaling pathways downstream to dopamine receptors. The focus of the present article, however, is the application of positron emission tomography (PET) to study the central pharmacokinetics of l-dopa. Radioligands with limited affinity for the dopamine D2 receptor are sensitive to changes in the levels of synaptic dopamine and can accordingly provide helpful insights into the magnitude and time course of dopamine release after l-dopa. Prolonged fluorodopa PET scans can be used to estimate the rate of dopamine turnover. Studies performed with these techniques have demonstrated increased dopamine turnover and increased but shorter duration release of dopamine after l-dopa as Parkinson's disease (PD) progresses, increased release of dopamine in patients with l-dopa-induced dyskinesia, and that aberrant patterns of dopamine release may actually predict the future development of motor fluctuations. Taken together, the studies provide in vivo validation for the hypothesis that pulsatile stimulation of dopamine receptors plays a critical role in the emergence of long-term motor complications of therapy. Similar approaches can be used to study the non-motor complications of PD and its treatment. Society.

What are the priorities in Parkinson's disease clinical research? A focus on motor complications, gait and cognition.

Motor complications, gait and balance disturbance, and cognitive impairment are problems frequently faced by patients with Parkinson's disease and by their treating physicians, and become more common as the disease progresses. Motor complications may be prevented or at least delayed by judicious use of levodopa, with other dopaminergic agents used for their levodopa-sparing effect. Increasingly, research has concentrated on nondopaminergic neurotransmitter systems, which may also have applicability in the management of gait and balance, and also in cognitive impairment in Parkinson's disease. This review, therefore, tackles these issues and discusses possible future treatments that may be available for the management of these challenging comorbidities.

Chapter Seven - Interaction of Adenosine Receptors with Other Receptors from Therapeutic Perspective in Parkinson's Disease

Altered dopaminergic neurotransmission in the basal ganglia is observed in Parkinson's disease (PD) and L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesias (LID). An attractive alternative for treating LID is to use adjunct drugs to modulate nondopaminergic neurotransmitter systems in the basal ganglia. For example, adenosine receptors have received attention over the past years for the treatment of PD and LID. Adenosine interacts closely with dopamine and plays an important role in the function of striatal GABAergic efferent neurons. Excitatory glutamatergic neurotransmission is also modulated by adenosine in the striatum. Hence, based on the unique cellular and regional distribution of this system, adenosine neurotransmission could have an important implication for the development of new therapeutic strategies targeting the basal ganglia disorders. Indeed, A2A adenosine receptor antagonists were shown to improve motor deficits in PD and to reduce the severity of LID. A2A receptor subtypes are selectively found on striatopallidal neurons and can couple with receptors of interest in PD, such as D2 dopamine and metabotropic glutamate receptor type 5 (mGlu5) receptors, and form functional heteromeric complexes. This chapter will review relevant studies investigating the role and contribution of adenosine receptor subtypes in pathophysiology of PD and LID. The interactions of adenosine receptors, especially A1 and A2A receptor subtypes, with other receptors implicated in the pathophysiology of PD and LID such as dopaminergic and glutamatergic receptors will be reviewed. The implication of these interactions in the development and expression of PD symptoms and LID needs further investigation to find novel drug targets.

Pathophysiology of somatosensory abnormalities in Parkinson disease

Changes in sensory function that have been described in patients with Parkinson disease (PD) can be either 'pure' disorders of conscious perception such as elevations in sensory threshold, or disorders of sensorimotor integration, in which the interaction between sensory input and motor output is altered. In this article, we review the extensive evidence for disrupted tactile, nociceptive, thermal and proprioceptive sensations in PD, as well as the influences exerted on these sensations by dopaminergic therapy and deep brain stimulation. We argue that abnormal spatial and temporal processing of sensory information produces incorrect signals for the preparation and execution of voluntary movement. Sensory deficits are likely to be a consequence of the dopaminergic denervation of the basal ganglia that is the hallmark of PD. A possible mechanism to account for somatosensory deficits is one in which disease-related dopaminergic denervation leads to a loss of response specificity, resulting in transmission of noisier and less-differentiated information to cortical regions. Changes in pain perception might have a different explanation, possibly involving disease-related effects outside the basal ganglia, including involvement of peripheral pain receptors, as well as structures such as the periaqueductal grey matter and non-dopaminergic neurotransmitter systems.

Pharmacological interventions to modulate attentional bias in addiction

Attentional bias in substance-dependent patients is the tendency to automatically direct attention to substance-related cues in the environment. Preclinical models suggest that attentional bias emerges as a consequence of dopaminergic activity evoked by substance-related cues. The aim of the current review is to describe pharmacological mechanisms underlying attentional bias in humans and to critically review empirical studies that aimed to modulate attentional bias in substance-dependent patients by using pharmacological agents. The findings of the reviewed studies suggest that attentional bias and related brain activation may be modulated by dopamine. All of the reviewed studies investigated acute effects of pharmacological agents, while measurements of chronic pharmacological treatments on attentional bias and clinically relevant measures such as relapse are yet lacking. Therefore, the current findings should be interpreted as a proof of principle concerning the role of dopamine in attentional bias. At the moment, there is too little evidence for clinical applications. While the literature search was not limited to dopamine, there is a lack of studies investigating the role of non-dopaminergic neurotransmitter systems in substance-related attentional bias. A focus on neurotransmitter systems such as acetylcholine and noradrenaline could provide new insights regarding the pharmacology of substance-related attentional bias.

Novel nondopaminergic targets for motor features of Parkinson's disease: Review of recent trials

Neurotransmitters other than dopamine are recognized as having modulatory roles within the basal ganglia and can influence the basal ganglia dopaminergic system to alter activity of the direct and indirect pathways. Many nondopaminergic neurotransmitter systems have been implicated in the mechanisms contributing to the motor features of Parkinson's disease (PD). Thus, it is now well established that neurotransmitter systems, including glutamatergic, GABAergic, cholinergic, noradrenergic, serotonergic, opioidergic, histaminergic, and adenosinergic systems, are affected in the pathogenesis of PD. Nondopaminergic neurotransmitter systems are thus targets for the development of novel therapies for motor symptoms and motor complications in PD. Over the last 5 years, more than 20 randomized, control trials (RCTs) in PD investigating drugs that target several of these nondopaminergic neurotransmitter systems for the treatment of motor features have been completed. There are at least 15 additional RCTs that are ongoing or planned. Here, we review these RCTs to highlight the potential nondopaminergic pharmacological therapies for treatment of motor features of PD. Nondopaminergic drugs are not expected to replace dopaminergic strategies, but further development of these drugs will likely yield novel approaches with positive clinical implications.

Interfacing basal ganglia models and Parkinson’s disease phenomenology: How can we translate the findings of electrophysiological studies from research to clinic

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms. There are several models both of basal ganglia (BG) function and their dysfunction in PD. Degeneration of the nigrostriatal dopaminergic pathway is the key pathological feature of PD, leading to classical motor symptoms, such as bradykinesia and rigidity. A dysfunction of structures other than BG, including cerebellum and brainstem, may be involved in the generation of tremor and axial symptoms, while the degeneration of non-dopaminergic neurotransmitter systems is a likely contributing factor of non-motor symptoms. BG models provide hypotheses testable by electrophysiological research in humans. In PD patients with implanted deep brain stimulators, activity from BG nuclei, i.e. the subthalamic nucleus the internal pallidal segment, and from the peduncolopontine nucleus may be directly recorded using depth electrodes. Non-invasive electrophysiological techniques allow the investigation of dysfunctional BG through interconnections with motor cortical areas, brainstem and spinal structures. Electrophysiological studies have revealed functional abnormalities at every level of the central nervous systems, including BG nuclei, motor cortex, cerebellum, brainstem and spinal cord. Despite the progress in electrophysiological characterization of PD, with particular advances in understanding the role of pathological BG oscillatory activity in generating bradykinesia, there is still a large gap in understanding the pathophysiological relevance of other electrophysiological findings in PD. Better insight into the relationship between electrophysiological abnormalities and motor and non-motor symptoms in PD is likely to have important clinical implications.

Fatty Acid Amide Hydrolase (FAAH) Inhibition Reduces l-3,4-Dihydroxyphenylalanine-Induced Hyperactivity in the 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Lesioned Non-Human Primate Model of Parkinson's Disease

Dopaminergic therapies remain the most efficacious symptomatic treatments for Parkinson's disease (PD) but are associated with motor complications, including dyskinesia, and nonmotor complications, such as psychosis, impulse control disorders (ICD), and dopamine dysregulation syndrome (DDS). Nondopaminergic neurotransmitter systems, including the endocannabinoid system, are probably critical to the development of these complications. The role of fatty acid amide hydrolase (FAAH) in mediating l-3,4-dihydroxyphenylalanine (L-DOPA)-induced behaviors was explored in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned marmoset model of PD. Pharmacodynamic and locomotor effects of the selective FAAH inhibitor [3-(3-carbamoylphenyl)phenyl] N-cyclohexylcarbamate (URB597) were assessed via bioanalytical (liquid chromatography-tandem mass spectrometry) and behavioral observation approaches. URB597 (3, 10, 30, or 60 mg/kg p.o.) increased plasma levels of the FAAH substrates N-arachidonoyl ethanolamide (anandamide), N-oleoyl ethanolamide, and N-palmitoyl ethanolamide by 10.3 ± 0.3-, 7.8 ± 0.2-, and 1.8 ± 0.1-fold (mean of URB597 groups ± S.E.M.), respectively, compared with vehicle (all p < 0.001) 4 h after administration. Treatment with L-DOPA (20 mg/kg s.c.) alleviated parkinsonism but elicited dyskinesia, psychosis-like-behaviors and hyperactivity, a potential correlate of ICD and DDS. During the 2 to 4 h after L-DOPA, corresponding to 4 to 6 h after URB597 administration, URB597 reduced total L-DOPA-induced activity and the magnitude of hyperactivity by 32 and 52%, respectively, to levels equivalent to those seen in normal animals. Treatment with URB597 (10 mg/kg p.o.) did not modify the antiparkinsonian actions of L-DOPA or L-DOPA-induced dyskinesia and psychosis. URB597 did not alter plasma L-DOPA levels and was without behavioral effects when administered alone. Inhibition of FAAH may represent a novel approach to reducing L-DOPA-induced side effects, such as ICD and DDS, while maintaining the antiparkinsonian benefits of L-DOPA treatment.

Quelles pistes pharmacologiques non-dopaminergiques pour le traitement de la maladie de Parkinson ?

It has become increasingly evident over the past years that the pathological process in Parkinson's disease extends well beyond the substantia nigra and involves non-dopaminergic neurotransmitter systems that mediate motor and non-motor symptoms. In this article, both the pathophysiology and the pharmacological management of these non-dopaminergic symptoms are discussed.

Dopaminergic and non‐dopaminergic pharmacological hypotheses for gait disorders in Parkinson’s disease

Gait disorders form one component of the axial disorders observed in Parkinson's disease (PD). Indeed, short steps with a forward-leaning stance are diagnostic criteria for PD in the early stages of the condition. Gait disorders also represent a major source of therapeutic failure in the advanced stages of PD (with the appearance of freezing of gait and falls) because they do not respond optimally to the two hand late-stage therapeutics--levodopa and electrical subthalamic nucleus (STN) stimulation. The late onset of doparesistance in these disorders may be linked to propagation of neurodegeneration to structures directly involved in gait control and to non-dopaminergic neurotransmitter systems. The coeruleus locus (a source of noradrenaline) is rapidly and severely affected, leading to a major motor impact. The pedunculopontine nucleus (PPN) and lateral pontine tegmentum (rich in acetylcholine) are both involved in gait. Degenerative damage to the serotoninergic raphe nuclei appears to be less severe, although serotonin-dopamine interactions are numerous and complex. Lastly, dopaminergic depletion leads to glutamatergic hyperactivity of the efferent pathways from the the STN to the PPN. However, the relationships between the various parkinsonian symptoms (and particularly gait disorders) and these pharmacological targets have yet to be fully elucidated. The goal of this review is to develop the various pathophysiological hypotheses published to date, in order to underpin and justify ongoing fundamental research and clinical trials in this disease area.

Non-dopaminergic treatments in development for Parkinson's disease

Non-dopaminergic treatments are increasingly being recognised as part of the therapeutic armamentarium for Parkinson's disease (PD). Clinical and pathological studies have shown that the disease extends beyond the substantia nigra pars compacta and involves various non-dopaminergic neurotransmitter systems that mediate both motor and non-motor symptoms that characterise PD. To date, several therapeutic strategies have been proposed to treat such symptoms. However, despite the significant morbidity associated with these symptoms, particularly non-motor symptoms, research into and drug development for problems such as mood and autonomic dysfunction remain scarce. Here, we review novel non-dopaminergic approaches that are in at least phase II clinical development for the treatment of PD.

Cognitive and behavioral dysfunction in Parkinson's disease: neurochemical and clinicopathological contributions.

The cognitive and behavioral sequelae (i.e., nonmotor profile) of Parkinson's disease (PD), with executive dysfunction and depression being most prominent, have typically been overshadowed due to an emphasis on motor symptomatology. The apparent categorization of PD as a disorder isolated to the dopaminergic system may be a generalization of the disease pathology. Dopamine therapy, used for the treatment of motor symptoms, has not consistently been shown to resolve nonmotor impairments. Research evidence indicates that nondopaminergic neurotransmitter systems (i.e., serotonergic, noradrenergic, & cholinergic) are disrupted in PD and may contribute to cognitive and behavioral dysfunction. Furthermore, Lewy bodies within cortical and subcortical structures can add to the nonmotor profile in PD. Pharmacological interventions for the treatment of cognitive and behavioral impairments associated with PD are few, especially for nondemented patients. The current review of the literature highlights evidence that associates nonmotor dysfunctions with neurochemical and clinicopathological correlates of PD.

Emergency psychiatry: extrapyramidal side effects in the psychiatric emergency service.

T benefits that neuroleptic medications provide in treating psychotic symptomatology in schizophrenia are well established (1). In addition, neuroleptic medications are often used to treat acute, psychotic episodes not related to schizophrenia, such as micropsychotic episodes among patients with personality disorders or posttraumatic stress disorder; acute psychosis from LSD, PCP, or cocaine intoxication; or psychotic states related to dementias and other neurological conditions. Neuroleptic medications are also often used for their acute sedative properties in treating agitated patients, both in psychiatric and nonpsychiatric settings. In tandem with the benefits of neuroleptic medications are significant risks associated with their use. These risks are primarily acute and chronic neurological adverse effects involving voluntary and involuntary musculature. This column focuses primarily on the acute side effects of neuroleptics, generally referred to as extrapyramidal side effects. These side effects are often seen as sequelae of acute neuroleptic treatment, often resulting in presentation to a psychiatric emergency service, such as an emergency room, a psychiatric emergency clinic in an emergency room, or a psychiatric consultation service in a general hospital. We discuss diagnosis, proposed etiology, and treatment of extrapyramidal side effects in the acute clinical setting.