James B. Lohr

Smoking and schizophrenia.

Several studies have shown that patients with schizophrenia have an extremely high prevalence of smoking, almost 90%, compared to only 33% in the general population and 45-70% in patients with other psychiatric diagnoses. The reasons for the high prevalence of smoking among schizophrenics is unknown, but it is likely that smoking behavior in schizophrenia may be a complex process, related to numerous interrelationships between the psychopathological, biochemical, and neuropharmacological aspects of smoking and of schizophrenia.

Candidate genes, pathways and mechanisms for bipolar (manic-depressive) and related disorders: an expanded convergent functional genomics approach

Identifying genes for bipolar mood disorders through classic genetics has proven difficult. Here, we present a comprehensive convergent approach that translationally integrates brain gene expression data from a relevant pharmacogenomic mouse model (involving treatments with a stimulant—methamphetamine, and a mood stabilizer—valproate), with human data (linkage loci from human genetic studies, changes in postmortem brains from patients), as a bayesian strategy of crossvalidating findings. Topping the list of candidate genes, we have DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of 32 kDa) located at 17q12, PENK (preproenkephalin) located at 8q12.1, and TAC1 (tachykinin 1, substance P) located at 7q21.3. These data suggest that more primitive molecular mechanisms involved in pleasure and pain may have been recruited by evolution to play a role in higher mental functions such as mood. The analysis also revealed other high-probability candidates genes (neurogenesis, neurotrophic, neurotransmitter, signal transduction, circadian, synaptic, and myelin related), pathways and mechanisms of likely importance in pathophysiology.

Oxidative Mechanisms and Tardive Dyskinesia

Tardive dyskinesia has been and continues to be a significant problem associated with long-term antipsychotic use, but its pathophysiology remains unclear. In the last 10 years, preclinical studies of the administration of antipsychotics to animals, as well as clinical studies of oxidative processes in patients given anti-psychotic medications, with and without tardive dyskinesia, have continued to support the possibility that neurotoxic free radical production may be an important consequence of antipsychotic treatment, and that such production may relate to the development of dyskinetic phenomena.In line with this hypothesis, evidence has accumulated for the efficacy of antioxidants, primarily vitamin E (α-tocopherol), in the treatment and prevention of tardive dyskinesia. Early studies suggested a modest effect of vitamin E treatment on existing tardive dyskinesia, but later studies did not demonstrate a significant effect. Because evidence has continued to accumulate for increased oxidative damage from antipsychotic medications, but less so for the effectiveness of vitamin E, especially in cases of long-standing tardive dyskinesia, alternative antioxidant approaches to the condition may be warranted. These approaches may include the use of antioxidants as a preventive measure for tardive dyskinesia or the use of other antioxidants or neuroprotective drugs, such as melatonin, for established tardive dyskinesia.

Conventional vs. Newer Antipsychotics in Elderly Patients

Elderly patients with schizophrenia and dementia patients with agitation are frequently candidates for antipsychotic treatment. Conventional neuroleptics have relatively little effect on negative symptoms and may cause considerable side effects, especially in elderly patients. The authors have found a 29% cumulative annual incidence of tardive dyskinesia (TD) in middle-aged and elderly outpatients treated with relatively low doses of conventional neuroleptics Newer antipsychotics are less likely to cause extrapyramidal symptoms and may be associated with a lower risk of TD. They are generally effective for both positive and negative symptoms and may also improve some aspects of cognition, but these drugs have their own side effects. Dosing requirements for elderly patients tend to be much lower than those for younger adults.

Free radicals and tardive dyskinesia

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Identification of blood biomarkers for psychosis using convergent functional genomics.

There are to date no objective clinical laboratory blood tests for psychotic disease states. We provide proof of principle for a convergent functional genomics (CFG) approach to help identify and prioritize blood biomarkers for two key psychotic symptoms, one sensory (hallucinations) and one cognitive (delusions). We used gene expression profiling in whole blood samples from patients with schizophrenia and related disorders, with phenotypic information collected at the time of blood draw, then cross-matched the data with other human and animal model lines of evidence. Topping our list of candidate blood biomarkers for hallucinations, we have four genes decreased in expression in high hallucinations states (Fn1, Rhobtb3, Aldh1l1, Mpp3), and three genes increased in high hallucinations states (Arhgef9, Phlda1, S100a6). All of these genes have prior evidence of differential expression in schizophrenia patients. At the top of our list of candidate blood biomarkers for delusions, we have 15 genes decreased in expression in high delusions states (such as Drd2, Apoe, Scamp1, Fn1, Idh1, Aldh1l1), and 16 genes increased in high delusions states (such as Nrg1, Egr1, Pvalb, Dctn1, Nmt1, Tob2). Twenty-five of these genes have prior evidence of differential expression in schizophrenia patients. Predictive scores, based on panels of top candidate biomarkers, show good sensitivity and negative predictive value for detecting high psychosis states in the original cohort as well as in three additional cohorts. These results have implications for the development of objective laboratory tests to measure illness severity and response to treatment in devastating disorders such as schizophrenia.

Videoconferencing psychotherapy: a systematic review.

Individuals with mental health problems may face barriers to accessing effective psychotherapies. Videoconferencing technology, which allows audio and video information to be shared concurrently across geographical distances, offers an alternative that may improve access. We conducted a systematic literature review of the use of videoconferencing psychotherapy (VCP), designed to address 10 specific questions, including therapeutic types/formats that have been implemented, the populations with which VCP is being used, the number and types of publications related to VCP, and available satisfaction, feasibility, and outcome data related to VCP. After electronic searches and reviews of reference lists, 821 potential articles were identified, and 65 were selected for inclusion. The results indicate that VCP is feasible, has been used in a variety of therapeutic formats and with diverse populations, is generally associated with good user satisfaction, and is found to have similar clinical outcomes to traditional face-to-face psychotherapy. Although the number of articles being published on VCP has increased in recent years, there remains a need for additional large-scale clinical trials to further assess the efficacy and effectiveness of VCP.

Possible Involvement of Free Radicals in Neuroleptic‐Induced Movement Disorders Evidence from Treatment of Tardive Dyskinesia with Vitamin E

Defined phenomenologically, tardive dyskinesia (TD) is a sign complex characterized by certain types of abnormal movements that are secondary to prolonged use of neuroleptic drugs.’-5 In recent years, TD has acquired greater importance to practitioners because of its occurrence in almost epidemic proportion and the evidence that its prevalence may be increasing?.4 TD was originally described as a “dyskinesie facio-bucco-lingui-masticatrice” (BLM or orofacial syndrome).* The concept has evolved to include nonrepetitive choreic and choreoathetoid movements of fingers, hands, and feet. It also includes choreoathetoid movements of the legs and trunk. Tardive dystonia6 and tardive akathisia’ may also be related to the TD complex. Tardive dyskinesia must be differentiated from other neurological disorders such as Huntington’s chorea, Sydenham’s chorea, drug-induced chorea, levodopa-induced dyskinesias, and the idiopathic and symptomatic dystonias. History of chronic use of neuroleptics is necessary before a diagnosis of TD can be made.

Shifting emphasis from pharmacogenomics to theragnostics

What will be the role of theragnostic patents in upstream and downstream biomarker research?

An fMRI study of affective state and medication on cortical and subcortical brain regions during motor performance in bipolar disorder

Structural neuroimaging studies have identified abnormalities in the basal ganglia in patients with bipolar disorder. Findings have been mixed with regard to affective state and have not elaborated on the role of medication on functional brain activity. The aims of the present study were to use functional magnetic resonance imaging (fMRI) to test whether depressed and manic bipolar disorder patients differ in terms of activity in cortical and subcortical brain areas and to examine the effects of psychotropic medication. Twenty-four bipolar disorder subjects and 13 healthy comparison subjects participated in an fMRI study of manual reaction time. Both manic and depressed subjects exhibited abnormally elevated blood oxygen level dependent BOLD responses in cortical and subcortical areas. Manic bipolar subjects had significantly higher BOLD responses in the left globus pallidus and significantly lower BOLD responses in the right globus pallidus compared with depressed bipolar patients. Correlational analyses revealed significant relationships between the severity of mania and activity within the globus pallidus and caudate. Patients off antipsychotic or mood-stabilizing medication exhibited significantly higher BOLD responses throughout the motor cortex, basal ganglia and thalamus compared with patients on these medications. These results suggest that affective state in bipolar disorder may be related to a disturbance of inhibitory regulation within the basal ganglia and that antipsychotics and/or mood stabilizers normalize cortical and subcortical hyperactivity.