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The implementation of a multisite, randomized, clinical psychopharmacologic trial involves a substantial investment of time and effort on the part of all participants. Because of their complexity, such clinical trials present unique methodological and design challenges. Indeed, it is not uncommon for such studies to conclude with uninterpretable results, due in part to such methodological pitfalls. It has been suggested that clarification of such methodologic dilemmas is one of the most important challenges facing the future of industry-sponsored psychopharmacologic drug development. Among the many factors that may contribute to problematic clinical trial results, error in measuring the phenomena being studied is of particular concern. In this article, we describe the outcome of an intensive series of interrater reliability training sessions for the 17-item Hamilton Depression Rating Scale conducted at the start of a Phase II multisite clinical drug trial. The data underscore the magnitude of error present in such a test setting and provide preliminary evidence for the potential effect of this problem on the detection of clinical change.

The sympathetic nervous system can modulate glucose levels through a variety of mechanisms, including inhibition of insulin release by alpha2-adrenergic receptors. Such effects could potentially confound measurements of brain glucose metabolism during studies of the central actions of sympathomimetic drugs. Plasma glucose, insulin, and sympathetic responses to alpha2 blockade were measured following infusion of idazoxan, a selective alpha2 antagonist, or placebo, in 33 healthy volunteers (idazoxan: n = 23, placebo: n = 10). These measures were compared with estimates of global brain metabolism obtained from positron emission tomography (PET) scans before and after the infusion. Glucose levels fell and fractional levels of insulin rose after idazoxan, compared with placebo. Relative increases in insulin correlated with increases in epinephrine after active drug. The increases in insulin are consistent with the hypothesized role of alpha2-adrenoceptors in regulating insulin release. Estimates of global brain glucose metabolism did not appear to be influenced by the modest changes in plasma glucose.

In recent years, research aimed at the elucidation of lithium's molecular mechanisms has focused on signal transduction pathways. This research has demonstrated that lithium has multiple effects on the phosphoinositide turnover signaling system. We have previously demonstrated that chronic (but not acute) in vitro exposure of HL60 cells to 1 mM lithium reduces both receptor and phorbol-ester-mediated Na+/H+ activity without affecting agonist-induced increases in intracellular Ca2+ or phosphoinositide breakdown, findings which suggest an attenuation of protein kinase C (PKC) function. The present study sought to measure the in vitro effects of lithium on PKC more directly and demonstrated that 5-day in vitro exposure of HL60 cells to either 1 mM or 10 mM lithium chloride dramatically reduces PKC alpha in both cytosolic and membrane fractions. Given the critical role of PKC in regulating neuronal signal transduction, these effects may play a major role in lithium's mood-stabilizing effects.

Natural products have a long history of being the sources for therapeutic drugs in medicine. Investigations of natural products also have the potential for enhancing our understanding about the pathophysiology and treatment of various disorders. The screening assays described here were conducted on the phytochemical and pharmacological profiles of natural products used to treat psychotic illnesses in Korean traditional medicine, which are eligibly archived in Tongeuibogam, a traditional medicinal book in Korea. Two rounds of radioligand receptor binding assays on natural products demonstrated that many plants show potent selectivity to various receptors, especially monoamine receptors presumed to be involved in mental disorders. Further studies for the pharmacologic activity of active ingredients and in vivo behavioral profiles focusing on the central nervous system (CNS) effects are currently under way with these plant extracts. These investigations may lead to the development of new psychotropic drugs with no serious side effects, a major concern for modern psychopharmacology.

The Psychotherapeutic Medications Development Program (PMDP) of the National Institute of Mental Health was established in 1990. The purpose of the PMDP is to improve, enhance, and speed the development of new medications and improve the therapeutic usefulness of existing medications for the treatment of mental illness. The PMDP will fulfill this mission by implementing four initiatives. In the drug discovery and development initiative, the PMDP will aid in the development of promising new drugs. This initiative will also include improving the therapeutic usefulness of existing medications. In the technology transfer initiative, PMDP will improve the technology transfer from academic and government researchers to the pharmaceutical industry; improve the dissemination of information concerning technology transfer opportunities as it pertains to psychotherapeutic medications; and enhance technology transfer by acting as a broker to bring interested parties together. For the third initiative, the PMDP will develop and maintain a capability to clinically evaluate psychotherapeutic medications. The PMDP will also act to facilitate the development and testing of new concepts and models of mental illness. There is a detailed description of the steps that are involved in developing a new chemical entity (NCE) from the conceptual stage to a medication that is approved for the treatment of a particular illness. The pharmaceutical industry estimates that this medication development process costs $238 million.

The animal literature provides many instances of gender differences in drug metabolism and/or response. However, there are inherent dangers in trying to generalize findings of either pharmacokinetic or pharmacodynamic gender differences to humans. The literature was searched for references to gender and pharmacokinetics of psychoactive drugs. Interest was primarily in whether sufficient data were available on humans to implicate a gender effect, given the large animal literature. There was a dearth of investigations to look for pertinent differences and many studies that examined gender differences appeared to do so incidentally. Some differences were identified that seemed hormonally influenced and age-related. The most compelling gender differences stem from data on research probes utilized to better understand psychiatric disease processes. The implications for women as psychoactive drug consumers are discussed.

Considerable evidence suggests that signal transduction pathways are targets of lithium (Li) action. A number of investigators have reported that Li attenuates both adenylate cyclase (AC) activity and phosphoinositide (PI) turnover in rodents and in humans, thus "dampening" these systems. We have studied selected components of these second-messenger systems in a series of clinical and preclinical investigations. To overcome confounding effects of alterations in mood state, we examined AC activity and G-protein ribosylation in peripheral blood cells from 10 healthy volunteers, prior to and following 14 days of Li administration. Basal and postreceptor [cesium fluoride (CsF) or Gpp(NH)p] stimulated AC activity were unaffected in lymphocytes. In contrast, both basal and stimulated AC activity in platelets were significantly augmented, compatible with an attenuation of Gi function. Ribosylation of platelet Gs by cholera toxin was unchanged, whereas that of Gi by pertussis toxin (PT) was increased. Given that undissociated G protein is the preferred substrate for PT, our results suggest that Li interferes with subunit dissociation and the subsequent activation of Gi. To determine if Li has similar effects on Gi in the central nervous system, we measured extracellular (EC) cyclic adenosine monophosphate (cAMP) in rat brain by in vivo microdialysis, revealing a dose-dependent increase in cAMP by norepinephrine (NE) antagonized by propranolol. Chronic (4-week) Li doubled basal EC cAMP, while decreasing the fractional response to 100 microM NE. Thus, using in vivo microdialysis, we observed the reported reduction in NE-stimulated AC activity, but only as a function of elevated basal cAMP. Increased basal AC activity has been observed following chronic Li in both humans and rat tissues but generally has not been considered relevant. The PI generating system is another proposed major target for Li that we have studied using an in vitro cell culture model of peripheral blood cells. Chronic (6-day) exposure of neutrophil-like HL60 cells to 1 mM LiCl did not affect agonist fMet-Leu-Phe (fMLP) induced PI turnover. In contrast, Li attenuated both agonist and phorbol ester stimulated Na+/H+ exchange, suggesting reduced protein kinase C (PKC) function. Western blot analysis revealed altered levels of PKC in both membrane and cytosolic fractions. The functional consequences of these complex effects on the two major signal transduction pathways and their interactions in the intact living organism remain to be elucidated.

Chronic treatment with a number of antidepressants results in a down-regulation and/or a desensitization of rat cortical beta-adrenergic receptors (beta ARs). Although these effects generally have been attributed to elevations in intrasynaptic norepinephrine via presynaptic mechanisms, the recent demonstration of similar changes in beta ARs following in vitro incubation of cultured cells with desipramine (DMI) suggests that direct, postsynaptic mechanisms may also be involved. To study these mechanisms, we incubated rat C6 glioma cells with 10 microM DMI for 1 or 5 days. DMI produced a significant reduction in beta AR density following chronic (but not acute) treatment (BMAX control = 1325 +/- 78 fmol/mg; DMI = 1179 +/- 96; p less than .05). Interestingly, the beta AR down-regulation was accompanied by an increase in KL/KH ratio (ratio of dissociation constants for the low- and high-affinity states of the receptor), suggesting that these drugs may stabilize the high-affinity complex. DMI treatment attenuated the cyclic adenosine monophosphate (cAMP) response to 1 microM isoproterenol (control = 540 +/- 82 pmol/mg/15 min; DMI = 335 +/- 64; p less than .05), but not to agents acting distal to the receptor (cholera toxin or forskolin). Coincubation of C6 cells with either the phospholipase A2 (PLA2) inhibitor mepacrine or the protein kinase C (PKC) inhibitor H7, during chronic treatment with DMI, blocked the down-regulation of beta ARs. Incubation of C6 cells with phorbol esters (PKC activators) also down-regulated beta ARs, effects that were nonadditive with those of DMI. Incubation with H7 alone resulted in an up-regulation of beta ARs, consistent with a tonic regulatory effect of PKC on beta ARs.(ABSTRACT TRUNCATED AT 250 WORDS)

One of the difficulties in pharmacotherapy of depression is the frequent need to make several dosage titrations before reaching the optimal therapeutic dosage. This problem has led to several experimental approaches for predicting a stable antidepressant maintenance dose from plasma concentration data collected shortly following a test dose. The theoretical basis for these methods is reviewed along with the results of clinical trials. It is concluded that accurate steady-state concentrations of cyclic antidepressants can be predicted from kinetic analysis of plasma concentrations obtained early in therapy. The most applicable drug for prospective dosing methods is nortriptyline with its widely accepted therapeutic plasma concentration range. Other drugs that also have substantial evidence for predicting the optimal dose from an early point in therapy include desipramine and imipramine. Predictive dosing methods are easily applied in the inpatient setting. Multiple data points obtained between 12 and 48 hours after the first dose are likely to give accurate predictions and provide clinically useful information. More widespread application of predictive approaches to dosage regimen design of antidepressant pharmacotherapy may lead to reduced hospitalization and cost savings.