An initial report of a new biological marker for bipolar disorder: P85 evoked brain potential

Objectives:  Progress toward understanding the neurobiological and genetic underpinnings of bipolar disorder has been limited by the scarcity of potential biological markers that predict its occurrence. A measure of the integrity of brain inhibitory function, sensory gating, measured using the amplitude of the evoked potential at 50 ms to the first of two paired clicks divided by the response to the second, has been characterized as a biological marker for schizophrenia. Currently, no such biological marker exists for bipolar disorder. The goal of this research was to determine how gating of an auditory brain potential at 85 ms (P85), not previously examined in sensory gating studies, differentiated control and patient groups.
Methods:  P50 and P85 auditory evoked potentials were collected from individuals diagnosed with schizoaffective disorder (n = 45), paranoid schizophrenia (n = 66), and bipolar I disorder (n = 42) using DSM-IV criteria and the Structured Clinical Interview for DSM-IV; and from 56 healthy controls.
Results:  The P85 gating ratio was significantly larger in the bipolar disorder group compared to each of the other groups ( F _3,204 = 5.47, p = 0.001, and post-hoc tests). The P50 gating ratio was significantly larger for the schizoaffective group than for the control group ( F _3,204 = 2.81, p = 0.040), but did not differ from the ratio for the schizophrenia, paranoid type (p = 0.08) and bipolar groups.
Conclusions:  The previously unstudied P85 gating ratio may provide a new marker specific to bipolar disorder. The findings will promote further studies to investigate the unique contribution of this measure as an endophenotype.     

Gating of a novel brain potential is associated with perceptual anomalies in bipolar disorder

Patterson JV, Sandman CA, Jin Y, Kemp AS, Potkin SG, Bunney WE Jr. Gating of a novel brain potential is associated with perceptual anomalies in bipolar disorder.
Bipolar Disord 2013: 00: 000–000. © 2013 John Wiley & Sons A/S.Published by Blackwell Publishing Ltd. Objectives: Our laboratory recently identified the P85 gating ratio as a candidate biomarker for bipolar disorder. In order to evaluate the phenomenological significance of P85 gating, the current study examined reports of perceptual anomalies and their relationship to the P50 and P85 physiological measures of sensory gating. Methods: Reports of perceptual anomalies on the Structured Clinical Interview to Assess Perceptual Anomalies were compared in patients meeting DSM‐IV criteria for paranoid schizophrenia (n = 66), schizoaffective disorder (n = 45), or bipolar I disorder (n = 42), and controls (n = 56), as well as their relationship with P85 and P50 gating. Results: The bipolar disorder group reported significantly more auditory, visual, and total anomalies than both the schizophrenia and control groups. The schizophrenia group also had more anomalies than the control group. Comparison of psychiatric subgroups revealed that the bipolar depressed, bipolar disorder with psychosis, and schizoaffective bipolar type groups reported the most anomalies compared to the other patient groups (bipolar disorder without psychosis, schizoaffective, bipolar manic). The total perceptual anomalies score and the P85 ratio significantly differentiated the bipolar disorder, schizoaffective, and paranoid schizophrenia groups from each other. Conclusions: These findings provide evidence of the phenomenological significance of P85. The results also yield further support not only for the P85 ratio, but also for increased reports of perceptual anomalies as possible markers for bipolar disorder.     

Possible mechanisms by which repeated clozapine administration differentially affects the activity of two subpopulations of midbrain dopamine neurons

Extracellular single-cell recording techniques were employed to study the mechanism of action of repeated oral clozapine administration on the in vivo spontaneous activity of substantia nigra (A9) and ventral tegmental area (A10) dopamine (DA)-containing neurons in the rat. Clozapine was observed to affect DA neurons differentially within these two regions when compared to haloperidol. Acute treatment (1 hr) with both drugs increased the number of spontaneously firing neurons in both A9 and A10. Chronic (21 day) treatment with haloperidol decreased the number of cells encountered in both regions, whereas repeated treatment with clozapine reduced the number of DA cells per track only in A10. In all cases, the silent DA neurons were inferred to be in a state of depolarization inactivation since they could be induced to discharge normally by the microiontophoretic application of the inhibitory neurotransmitter gamma-aminobutyric acid. These effects were not due to an effect of chloral hydrate anesthesia since they were also observed in gallamine-paralyzed, artificially respired animals. Chronic co-administration with haloperidol of either an anticholinergic (trihexyphenidyl) or the alpha 1-norepinephrine (NE) receptor antagonist, prazosin, but not an alpha 2-NE antagonist, RX781094, resulted in a differential effect on A9 and A10 DA neurons identical to that observed with repeated clozapine administration alone. Thus, chronic treatment with these combinations of drugs resulted in the depolarization inactivation of only A10 cells. These data suggest that anticholinergic and/or alpha 1-NE-blocking properties of clozapine may, in part, mediate its differential effects on A9 and A10 midbrain DA neurons.     

Unilateral transplantation of human fetal mesencephalic tissue into the caudate nucleus of patients with Parkinson's disease.

BACKGROUND. Parkinson's disease is characterized by the loss of midbrain dopamine neurons that innervate the caudate and the putamen. Studies in animals suggest that fetal dopaminergic neurons can survive transplantation and restore neurologic function. This report compares the clinical results in four case patients with severe Parkinson's disease who underwent stereotaxic implantation of human fetal ventral mesencephalic tissue in one caudate nucleus with the results in a control group of similar subjects assigned at random to a one-year delay in surgery. METHODS. Each case patient received cryopreserved tissue from one fetal cadaver (gestational age, 7 to 11 weeks). Before implantation, adjacent midbrain tissue underwent microbiologic, biochemical, and viability testing. Cyclosporine was administered for six months postoperatively. RESULTS. The procedure was well tolerated. Three case patients showed bilateral improvement on motor tasks, as assessed on videotape, and were more functional in the activities of daily living, as assessed by themselves and neurologists, during both optimal drug therapy and "drug holiday" periods. One case patient, who died after four months from continued disease progression, had striatonigral degeneration at autopsy. In the patients who received transplants, optimal control was achieved with a lower dose of antiparkinsonian medications, whereas the controls required more medication. Positron-emission tomography with [18F]fluorodopa before and after surgery in one patient revealed a bilateral restoration of caudate dopamine synthesis to the range of normal controls, but continued bilateral deficits in the putamen. CONCLUSIONS. Although the case patients continued to be disabled by their disease, unilateral intracaudate grafts of fetal tissue containing dopamine diminished the symptoms and signs of parkinsonism during 18 months of evaluation.     

Failure of Hemodialysis to Diminish Psychotic Behavior in Schizophrenia: Behavioral and Psychophysiological Evaluation

In a double-blind sham replacement study, eight drug-free schizophrenic patients underwent 10 active and 10 sham hemodialysis for 20 weeks. At the end of the 10 active dialyses, none of the patients appeared to be improved in psychotic, affective, or social symptoms. Active dialysis was associated with a "startle" response in heart rate and skin conductance to auditory stimuli, while sham dialysis was associated with an "orienting" response. Night-recorded sleep electroencephalography was unaffected by active dialysis. Spinal fluid beta-endorphin-like immunoreactivity levels were unchanged after active treatment. The behavioral improvements reported in other studies may be related to "stress," psychotherapeutic support, spontaneous remissions, neuroleptic withdrawal, denial of symptoms, or diagnostic differences. This study did not confirm the claims for hemodialysis as a specific therapeutic intervention in schizophrenia.