Anton J. M. Loonen

Circuits regulating pleasure and happiness: the evolution of reward-seeking and misery-fleeing behavioral mechanisms in vertebrates.

The very first free-moving animals in the oceans over 540 million years ago must have been able to obtain food, territory, and shelter, as well as reproduce. Therefore, they would have needed regulatory mechanisms to induce movements enabling achievement of these prerequisites for survival. It can be useful to consider these mechanisms in primitive chordates, which represent our earliest ancestors, to develop hypotheses addressing how these essential parts of human behavior are regulated and relate to more sophisticated behavioral manifestations such as mood. An animal comparable to lampreys was the earliest known vertebrate with a modern forebrain consisting of old and new cortical parts. Lampreys have a separate dorsal pallium, the forerunner of the most recently developed part of the cerebral cortex. In addition, the lamprey extrapyramidal system (EPS), which regulates movement, is modern. However, in lampreys and their putative forerunners, the hagfishes, the striatum, which is the input part of this EPS, probably corresponds to the human centromedial amygdala, which in higher vertebrates is part of a system mediating fear and anxiety. Both animals have well-developed nuclear habenulae, which are involved in several critical behaviors; in lampreys this system regulates the reward system that reinforces appetitive-seeking behavior or the avoidance system that reinforces flight behavior resulting from negative inputs. Lampreys also have a distinct glutamatergic nucleus, the so-called habenula-projection globus pallidus, which receives input from glutamatergic and GABAergic signals and gives output to the lateral habenula. Via this route, this nucleus influences midbrain monoaminergic nuclei and regulates the food acquisition system. These various structures involved in motor regulation in the lampreys may be conserved in humans and include two complementary mechanisms for reward reinforcement and avoidance behaviors. The first system is associated with experiencing pleasure and the second with happiness. The activities of these mechanisms are regulated by a tract running via the habenula to the upper brainstem. Identifying the human correlate of the lamprey habenula-projecting globus pallidus may help in elucidating the mechanism of the antidepressant effects of glutamatergic drugs.

Hypothermia following antipsychotic drug use

ObjectiveHypothermia is an adverse drug reaction (ADR) of antipsychotic drug (APD) use. Risk factors for hypothermia in ADP users are unknown. We studied which risk factors for hypothermia can be identified based on case reports.MethodCase reports of hypothermia in APD-users found in PUBMED or EMBASE were searched for risk factors. The WHO international database for Adverse Drug Reactions was searched for reports of hypothermia and APD use.ResultsThe literature search resulted in 32 articles containing 43 case reports. In the WHO database, 480 reports were registered of patients developing hypothermia during the use of APDs which almost equals the number of reports for hyperthermia associated with APD use (n = 524). Hypothermia risk seems to be increased in the first days following start or dose increase of APs. APs with strong 5-HT2 antagonism seem to be more involved in hypothermia; 55% of hypothermia reports are for atypical antipsychotics. Schizophrenia was the most prevalent diagnosis in the case reports.ConclusionEspecially in admitted patients who are not able to control their own environment or physical status, frequent measurements of body temperature (with a thermometer that can measure low body temperatures) must be performed in order to detect developing hypothermia.

New insights into the mechanism of drug-induced dyskinesia.

Dyskinesia is an extrapyramidal movement disorder characterized by involuntary, repetitive, irregular motions that affect the mouth and face and/ or the limbs and trunk. Tardive dyskinesia (TD) is a well-known complication of long term treatment with antipsychotic drugs. Dyskinesia is also induced with levodopa, a treatment for Parkinsons disease,and it occurs spontaneously as a symptom of Huntingtons disease. Research on the pathogenesis of TD has focused on a dysfunction of either the dopaminergic or serotonergic system. However, recent evidence has suggested that we should focus on the possible damage of GABAergic medium spiny neurons (MSNs). MSNs are the first station in the corticostriato-thalamo-cortical circuit that regulates the amplitude and velocity of movements. Two pathways can be distinguished in this circuit: a direct pathway, which increases movements (hyperkinesia), and an indirect pathway,which decreases movements (hypokinesia). Both pathways are activated by glutamatergic corticostriatal neurons. Here,we discuss some evidence that supports the hypothesis that indirect pathway MSNs are damaged in dyskinesia.

Measuring movement disorders in antipsychotic drug trials - The need to define a new standard

The history of modern antipsychotic drugs began in 1952 with the discovery of the specific calming effects of chlorpromazine (RP4560) in agitated manic patients by Delay and Deniker at La Hôpital Sainte-Anne in France. It was almost immediately recognized that these drugs induced a movement disorder with symptoms similar to Parkinson disease. The first formal report of extrapyramidal side effects was published in 1954. The occurrence of dyskinesias associated with long-term use of neuroleptics was reported by Sigwald et al in 1959. The term atypical refers to antipsychotic drugs that induce fewer extrapyramidal side effects than classic antipsychotic drugs. By 1970, the 3 available atypical antipsychotic drugs were thioridazine, sulpiride, and clozapine, introduced in 1958, 1968, and 1969. However, in 1975, clozapine was withdrawn from the market in most countries because of reports of agranulocytosis in patients taking the drug. Thioridazine and sulpiride were not very potent, and they were associated with other conditions, such as retinitis pigmentosa in the case of thioridazine and hyperprolactinemia in the case of sulpiride. However, to the merit of Kane et al, the unique properties of clozapine in treatment-resistant schizophrenia were rediscovered. The drug was reintroduced and became widely used, despite its limitations. As it became evident that clozapine fulfilled a specific clinical need, the pharmaceutical industry developed a series of other atypical or modern antipsychotic drugs. All of these drugs share the common property that they induce parkinsonism to a lesser degree than classic antipsychotic drugs. Haloperidol in fairly high doses is a prototype of a classic, parkinsonism-inducing drug, although there is debate as to whether this is true for lower doses. It is even less certain that the atypical drugs are less likely to cause extrapyramidal side effects other than parkinsonian rigidity. Antipsychotic drugs are indicated in patients with schizophrenia or schizoaffective disorders. However, antipsychotics are also used to treat other psychotic conditions and for the general management of severe agitation in psychiatric patients. During the last few years, atypical antipsychotic drugs have assumed a firm position in the treatment of bipolar disorders, and this has resulted in 2 new problems with respect to treatmentinduced movement disorders. First, there is some evidence that patients with bipolar disorder are particularly vulnerable to tardive movement disorders. Second, the other drugs that are used for treating bipolar disorder, including lithium and anticonvulsant and antidepressant drugs, cause movement disorders other than those associated with the use of classic antipsychotic drugs. These movement disorders are usually not evaluated in clinical trials that evaluate the effects of antipsychotic drugs, even when lithium and/or anticonvulsants are used for comparison. Guest Editorial

Nitric oxide and neopterin in bipolar affective disorder.

Background: There is an increasing interest in the role of nitric oxide (NO) and pterines in the pathophysiology of neuropsychiatric disorders. The results so far show an inconsistent pattern. Methods: In the present study, neopterin and a measure of NO synthesis in plasma of symptomatic and euthymic bipolar affective patients were compared to those of patients with a major depression and healthy controls. As an index of NO synthesis, the ratio of the amino acids citrulline and arginine (Cit-Arg ratio) was calculated. Neopterin is a bypass product in the synthesis of tetrahydrobiopterin, which is a cofactor of NO synthase. Results: The results indicate that both neopterin and the Cit-Arg ratio are decreased in bipolar affective patients, irrespective of their symptomatic status. In addition, an association between the values of the Cit-Arg ratio and the neopterin level was observed, which is suggestive for a low tetrahydrobiopterin activity. Conclusion: NO formation may be endangered in bipolar affective disorder.

Improvement of care for the physical health of patients with severe mental illness: a qualitative study assessing the view of patients and families

BackgroundPatients with severe mental illness (SMI) experience more physical comorbidity than the general population. Multiple factors, including inadequate seeking of healthcare and health care related factors such as lack of collaboration, underlie this undesirable situation. To improve this situation, the logistics of physical health care for patients with SMI need to be changed. We asked both patients and their families about their views on the current organization of care, and how this care could be improved.MethodsGroup and individual interviews were conducted with patients and family of patients to explore their needs and preferences concerning the care for the physical health of patients with SMI, and to explore the shortcomings they had experienced. Using thematic analysis, responses were firstly divided into common topics, after which these topics were grouped into themes.ResultsThree major themes for the improvement of the physical care of patients with SMI were found. Firstly, the reduced ability of patients with SMI to survey their own physical health interests requires health care that is tailored to these needs. Secondly, the lack of collaboration amongst mental health care professionals and general practitioners (GPs) hinders optimal care. Thirdly, concerns were expressed regarding the implementation of monitoring and supporting a healthy lifestyle. Patients with SMI welcome this implementation, but the logistics of providing this care can be improved.ConclusionsAn optimal approach for caring for the physical health of patients with SMI requires a professional approach, which is different to the routine care provided to the general public. This approach can and should be accomplished within the usual organizational structure. However, this requires tailoring of the health care to the needs of patients with SMI, as well as structural collaboration between mental health care professionals and GPs.

The Mechanism of Drug-induced Akathisia

Akathisia is a movement disorder characterized by an inner sense of unease, unrest, and dysphoria. It can result in an inability to stand, sit, or lie still, and an intense urge to move around. It is a common side effect of drugs, such as antipsychotics and serotonin selective reuptake inhibitors (SSRIs), but it also occurs spontaneously in patients with Parkinsons disease. Several lines of evidence suggest that akathisia can be attributed to low activity of dopaminergic projections from the midbrain to the ventral striatum. However, the exact pathophysiological mechanism of this extrapyramidal symptom remains unclear. This article describes a possible mechanism for drug-induced akathisia based on the differential functions of the core and shell portions of the nucleus accumbens. These ideas arise from contemporary concepts regarding the mechanisms of compulsion, impulsivity, and depression.

Visualizing Pharmacological Activities of Antidepressants: A Novel Approach

Antidepressants have different receptor binding profiles, which are related to therapeutic action and adverse drug reactions. We constructed a model to classify antidepressants on the basis of their binding properties of most common transporter- and receptor sites. Receptor binding was quantified by calculating receptor occupancy for the 5-HT (serotonin) reuptake transporter, norepinephrinic reuptake transporter, 5-HT2C-receptor, M3-receptor, H1-receptor and 1- receptor. To identify groups of antidepressants that show similar patterns of receptor occupancy for different receptors, hierarchical cluster analysis (HCA) and principle component analysis (PCA) were used. In addition, to visualize (a)symmetry between binding profiles of antidepressants, radar plots were constructed. On the basis of both analyses, four clusters of antidepressants which exert similar pharmacological properties were identified. Potentially, this model could be a helpful tool in medical practice and may be used as a prediction model for adverse effects of drugs entering the market.

The role of the habenula in the transition from reward to misery in substance use and mood disorders

The habenula (Hb) is an evolutionary well-conserved structure located in the epithalamus. The Hb receives inputs from the septum, basal ganglia, hypothalamus, anterior cingulate and medial prefrontal cortex, and projects to several midbrain centers, most importantly the inhibitory rostromedial tegmental nucleus (RMTg) and the excitatory interpeduncular nucleus (IPN), which regulate the activity of midbrain monoaminergic nuclei. The Hb is postulated to play a key role in reward and aversion processing across species, including humans, and to be implicated in the different stages of transition from recreational drug intake to addiction and co-morbid mood disorders. The Hb is divided into two anatomically and functionally distinct nuclei, the lateral (LHb) and the medial (MHb), which are primarily involved in reward-seeking (LHb) and misery-fleeing (MHb) behavior by controlling the RMTg and IPN, respectively. This review provides a neuroanatomical description of the Hb, discusses preclinical and human findings regarding its role in the development of addiction and co-morbid mood disorders, and addresses future directions in this area.

Circuits regulating pleasure and happiness in major depression

The introduction of selective serotonin reuptake inhibitors has gradually changed the borders of the major depression disease class. Anhedonia was considered a cardinal symptom of endogenous depression, but the potential of selective serotonin reuptake inhibitors to treat anxiety disorders has increased the relevance of stress-induced morbidity. This shift has led to an important heterogeneity of current major depressive disorder. The complexity can be disentangled by postulating the existence of two different but mutually interacting neuronal circuits regulating the intensity of anhedonia (lack of pleasure) and dysphoria (lack of happiness). These circuits are functionally dominated by partly closed limbic (regulating misery-fleeing behaviour) and extrapyramidal (regulating reward-seeking behaviour) cortico-striato-thalamo-cortical (CSTC) circuits. The re-entry circuits include the shell and core parts of the accumbens nucleus, respectively. Pleasure can be considered to result from finding relief from the hypermotivation to exhibit rewarding behaviour, and happiness from finding relief from negative or conflicting circumstances. Hyperactivity of the extrapyramidal CSTC circuit results in craving, whereas hyperactivity of the limbic system results in dysphoria.