M. Hariharan

Caffeine and human cerebral blood flow: A positron emission tomography study

Positron emission tomography (PET) was used to quantify the effect of caffeine on whole brain and regional cerebral blood flow (CBF) in humans. A mean dose of 250 mg of caffeine produced approximately a 30% decrease in whole brain CBF; regional differences in caffeine effect were not observed. Pre-caffeine CBF strongly influenced the magnitude of the caffeine-induced decrease. Caffeine decreased paCO2 and increased systolic blood pressure significantly; the change in paCO2 did not account for the change in CBF. Smaller increases in diastolic blood pressure, heart rate, plasma epinephrine and norepinephrine, and subjectively reported anxiety were also observed.

Alpha2-adrenoceptor status in obsessive-compulsive disorder

Ten patients with obsessive-compulsive disorder (OCD) and 13 normal control subjects received intravenous infusions of 2 X 10(-6) g/kg of clonidine and normal saline on separate days. Responses to the drug relating to plasma growth hormone (GH), 3-methoxy-4-hydroxyphenylglycol (MHPG), heart rate, blood pressure, and several symptoms were determined. Additionally, platelet alpha 2-adrenoreceptor binding was measured in most of the subjects. GH, MHPG, blood pressure, and heart rate responses to clonidine did not differ between groups. As expected, patients reported more symptoms than normal subjects, and clonidine was sedating for both groups. Patients did not differ from normal subjects in the symptom response to clonidine. The maximum number of binding sites (Bmax) for tritiated clonidine was significantly greater in OCD patients than in normals. This pattern of alpha 2-adrenoreceptor status is different than the patterns in major depression and panic anxiety.

Positive and negative symptoms in schizophrenia and the dexamethasone suppression test

Although the Dexamethasone Suppression Test (DST) was originally proposed as a specific marker for major depressive disorder (Carroll et al. 1981), several recent studies have reported high rates of DST nonsuppression in schizophrenic patients, ranging from 22% to 73%. DST nonsuppression in schizophrenia has been attributed to depressive symptomatology (Munro et al. 1983), negative symptomatology (Coppen et al. 1983; Shima et al. 1986), subtype differences (Banki et al. 1984), episodic course, and good prognosis (Targum 1983). Investigations have so far yielded discrepant findings, prompting at least one author (Myers 1984) to suggest

Nicotinic Effects of Antidepressants

Tricyclic antidepressants (TCAs) bind to muscarinic cholinergic receptors (mAChRs) and produce biochemical and physiological evidence of the blockade of muscarinic mechanisms.1 Supersensitization of these mechanisms is a regularly occurring effect of agents that directly block access of acetylcholine to the post-synaptic mAChR or inhibit its release from presynaptic cholinergic neurons.2 Treatment with amitriptyline (AMI) 10 mg/kg i.p. twice daily for 7 days or more enhances sensitivity to the hypothermic effects of oxotremorine.3 Although the muscarinic effects of TCAs have been investigated, the influences of these and other antidepressants on parameters influenced by nicotinic mechanisms have received minimal attention.

PLATELET ALPHA 2-ADRENORECEPTORS, CATECHOLAMINES, HEMODYNAMIC VARIABLES, AND ANXIETY IN PANIC PATIENTS AND THEIR ASYMPTOMATIC RELATIVES

The objectives of this study were to a) replicate our prior finding of a decreased number (Bmax) of platelet alpha2-adrenoreceptors in panic disorder, b) determine if binding is also decreased in asymptomatic first-degree relatives of panic patients (known to be at increased risk for developing panic), and c) evaluate the effect of treatment on the presumptive decrease in binding (ie, is the decrease a state or a trait marker for panic?). Panic patients had clonidine and yohimbine platelet-binding assays, symptom ratings, and measurement of lying and standing plasma epinephrine, norepinephrine, systolic and diastolic blood pressure, and heart rate before treatment, after approximately 2 months of medication (fluoxetine, tricyclics, or alprazolam) and/or cognitive behavioral treatment, and after symptom remission while drug free; normal subjects had determinations of the same measures at approximately the same time intervals. Relatives of both groups had one determination only of all measures. Tritiated clonidine binding was decreased and lying heart rate was increased in patients before treatment. Magnitude of binding decrease was correlated with symptom severity and standing norepinephrine. No binding abnormality was seen in first-degree relatives of patients. Treatment increased clonidine binding in patients. Both patients and relatives of patients showed significantly increased standing plasma norepinephrine in comparison to controls. There is a state-related decrease in binding, associated with symptom severity and norepinephrine, in panic disorder. Abnormal reactivity of norepinephrine to standing might be a marker for increased likelihood of panic development in individuals at risk.

Determination of Clozapine and Its Two Major Metabolites in Human Serum by Liquid Chromatography Using Ultraviolet Detection

Abstract A new, simple, reverse phase, and highly reproducible HPLC-UV method that has all the comprehensive features of good column, mobile phase, internal standard and extraction has been developed for the assay of clozapine (CLZ), norclozapine (NCLZ) and clozapine-N-oxide (CLZNO) in human serum. The method is very easy to adapt, overcomes the problems of earlier methods and is very economical. Amoxapine is the internal standard. All three analytes are extracted from alkaline serum using ethyl acetate and the absolute extraction efficiency is ∼95%. The UV detector is set at 230 nm. The mobile phase is a mixture of phosphate buffer (0.05M, pH 2.7), acetonitrile and methanol (62:20:18 v/v) and contains 2.5 mL triethylamine per liter of solution. The detection limit of the method is 2 ng/mL for CLZ and NCLZ and 4 ng/mL for CLZNO. The mean CV for the method is 5%.

Chronic treatment with lithium produces supersensitivity to nicotine

the evoked potential in acute schizophrenics durPritchard WS (1986): Cognitive event-related potening a test of sustained attention. Biol Psychiatry tials in schizophtenics. Psycho1 Bull 100:43-66. 15:9-20. Walker E, Shaye J (1982): Familial schizophrenia: Pfefferbaum A, Wenegrat BG, Ford JM, Roth W’I’, A predictor of neuromotor and attentional abnorKopell BS (1984): Clinical application of the P3 malities in schizophrenia. Arch Gen Psychiatry component of event-related potentials. II. De39:1153-1156. mentia, depression and schizophrenia. Electroencephalogr Clin Neurophysiol59:104-124.

Liquid Chromatographic Coulometric Assay and Preliminary Pharmacokinetics of Yohimbine in Man

Abstract Earlier HPLC fluorometric, ultraviolet and amperometric detector methods are not simple and sensitive for the assay of yohimbine for both therapeutic drug monitoring and pharmacokinetic studies. A simple and a very senitive HPLC coulometric assay has been developed using a C-8 column and a mobile phase of water and acetonitrile 65:35 (v/v) containing 1.8g/L of tetraethylammonium perchlorate. the optimum oxidation potential for yohimbine was 0.8 V against a Ag/AgCl electrode. Reserpiline was used as the internal standard. the sensitivity of the assay is 200 pg using 1 mL of plasma. the average inter-assay CV was 7 % and the recovery relative to the internal standard was 100 %. the assay method was used to determine the pharmacokinetics of the drug after an oral and IV dose in an individual.

A Simple, Sensitive Liquid Chromatographic Assay of cis -thiothixene in Plasma with Coulometric Detection

A novel, simple, and very sensitive liquid-chromatographic assay with a coulometric detector has been developed for quantitating cis-thiothixene (CTX) in human plasma. A reverse phase, 5-microns cyano column (25 x 0.46 cm), a mobile phase of phosphate buffer (pH 2.5) and acetonitrile (40/60 by vol), and a coulometric detector are used for the separation of CTX, and the internal standard, trifluoperazine. CTX and trifluoperazine are extracted from alkalinized plasma into n-pentane-isopropanol (95/5 by vol) and purified by back extraction into perchloric acid. The optimum oxidation potential for the analytes is +0.8 V versus an Ag/AgCl electrode. The detection limit for CTX is 200 pg using 1 mL of plasma and CTX concentrations are linear from 0 to 40 micrograms/L. The average interassay CV is 9%, and the mean recovery is 99% relative to the internal standard. Possible interferences from various psychiatric and common drugs in the assay have been studied. The assay method was validated by determining the concentration of CTX in the plasma of 100 schizophrenic patients.

Noradrenergic response to intravenous yohimbine in patients with depression and comorbidity of depression and panic

Adrenergic response following infusions of yohimbine or normal saline was evaluated in 9 control subjects, 8 patients suffering from a major depressive episode (MDE), and 12 patients suffering from concurrent MDE and panic disorder (MDE + P). Blood was drawn at -20, 0, 5, 10, 20, 45, and 90 min following the infusions, and assayed for norepinephrine (NE) and 3-methoxy-4-hydroxy-phenyl glycol (MHPG). Although the patient groups exhibited higher baseline NE concentrations, and a greater NE area under the plasma concentration versus time curve (AUC0-90) during the yohimbine infusion, the differences were not statistically significant. Baseline NE was significantly correlated with the NE AUC0-90 in all three groups, suggesting that, although the NE system may be dysregulated in the MDE and MDE + P patients, the NE system still appears to respond somewhat predictably following a challenge, even though the actual magnitude of response may vary.