Davis Jm

Depot antipsychotic drugs. Place in therapy.

SummaryThe pharmacokinetics of depot antipsychotic medications are such that an intramuscular injection given at intervals of from 1 to 4 weeks will produce adequate plasma concentrations that are sufficient to prevent relapse over the dosage interval. Such medication is useful in patients who do not reliably take their oral medication. The pharmacokinetics and clinical actions of various depot formulations of antispychotic drugs have been extensively studied.Unfortunately, patients who do not reliably take their oral medications are unlikely to volunteer for controlled studies. This is because the same factors that influence a patient to not cooperate with the physician in taking the medication as prescribed will also interfere with their willingness to volunteer for research protocols. Thus, evidence from blinded controlled trials may not necessarily reflect the actual patient population at risk.We feel that particularly important evidence of efficacy of depot vs oral medication comes from mirror-image studies. In these trials, the number of hospitalisations after initiation of depot medication is compared with that observed when the patient was solely taking oral medication. Studies of this type show that depot medication substantially reduces the rate of relapse.There is considerable evidence about how long depot medications should be used. For many patients, depot medication to prevent relapse in schizophrenia should be used for the life of the patient. As the conventional antispychotic agents are replaced by a new generation of agents, the need for depot formulations will continue, and the knowledge gained about the current formulations should transfer to future generations of drugs.

Epigenetic mechanisms expressed in basal ganglia GABAergic neurons differentiate schizophrenia from bipolar disorder

In the cerebral prefrontal cortex (PFC), DNA-methyltransferase 1 (DNMT1), the enzyme that catalyzes the methylation of cytosine at carbon atoms in position 5 in CpG dinucleotides, is expressed selectively in GABAergic neurons and is upregulated in layers I and II of schizophrenia (SZ) and bipolar disorder patients with psychosis (BDP). To replicate these earlier findings and to verify whether overexpression of DNMT1 and the consequent epigenetic decrease of reelin and glutamic acid decarboxylase (GAD) 67 mRNA expression also occur in GABAergic medium spiny neurons of the caudate nucleus (CN) and putamen (PT) of SZ and BDP, we studied the entire McLean 66 Cohort (Harvard Brain Tissue Resource Center, McLean Hospital, Belmont, MA) including SZ and BDP, which were matched with nonpsychiatric subjects. The data demonstrate that in GABAergic medium spiny neurons of CN and PT, unlike in GABAergic neurons of layer I and II PFC, the increased expression of DNMT1 and the decrease of reelin and GAD67 occur in SZ but not in BDP. This suggests that different epigenetic mechanisms must exist in the pathogenesis underlying SZ and BDP and implies that these disorders might involve two separate entities that are characterized by a well-defined neuropathology.

APPLICATION OF MODERN PSYCHOMETRIC THEORY IN PSYCHIATRIC RESEARCH

This paper describes the general statistical theory of item-response modeling as developed in the fields of statistics and education. Generalization of these procedures for application in the analysis of psychiatric rating scales is the focus of this paper. Questions of unidimensionality vs multidimensionality and choice of distributional transform (logistic vs normal) are both discussed and statistically examined using data on the Beck Depression Inventory (BDI). Application of these models to the BDI revealed two subscales that maximally differentiate high and low levels of depression in psychiatric and medically ill patients respectively. There was considerable but not complete overlap between the two subscales. These statistical models are found to have desirable properties when used to analyze psychiatric rating scales and provide a refinement over existing techniques of classical test theory and factor analysis.

Plasma and CSF HVA before and after pharmacological treatment

Plasma and cerebrospinal fluid (CSF) levels of the major dopamine metabolite homovanillic acid (HVA) were measured in psychiatric patients after an average washout period of 19 days, and again after 4 weeks of pharmacological treatment. Absolute values of plasma HVA did not correlate with absolute values of CSF HVA either at baseline or after treatment. However, changes in plasma HVA were highly correlated with changes in CSF HVA. Further, while baseline levels of plasma and CSF HVA were not significantly correlated with baseline clinical measures, clinical improvement was associated with decreases in both plasma and CSF HVA. This reached statistical significance for the plasma HVA level/clinical response relationship.

Consistent evidence for a biological subtype of depression characterized by low CSF monoamine levels

ABSTRACT Analysis of previously published CSF monoamine data has revealed statistical evidence for a biological subtype of depression, characterized by abnormally low CSF‐5HIAA and CSF HVA. Using maximum likelihood gaussian mixture analysis we were able to resolve the empirical frequency distributions of both CSF HVA and CSF 5‐HIAA into two component normal mixtures. Simultaneous analysis of both CSF 5‐HIAA and CSF HVA revealed a two component bivariate normal mixture distribution in which 35% of the depressed patient sample were classified in the low subgroup. No evidence for mixture distributions was found in controls. Analysis of CSF MHPG revealed a single component normal distribution with virtually identical mean and variance in both patients and controls. These results are shown to be virtually identical to parallel analyses conducted on CSF monoamine data collected as part of the NIMH collaborative study on the psychobiology of depression study.

Stress, depression, and mania: relationship between perceived role of stressful events and clinical and biochemical characteristics

We investigated the perceived role of stressful events in episodes of major affective disorder in patients studied in the NIMH Clinical Research Branch Collaborative Program on the Psychobiology of Depression (Biological Studies). Using items from the Schedule for Affective Disorders and Schizophrenia (SADS), episodes were divided into environment‐sensitive (high perceived role of stressful events) and autonomous (minimal or no perceived role of stressful events). Patients with environment‐sensitive episodes had fewer previous episodes and a longer index episode. The groups did not differ with respect to age, gender, education, socioeconomic group, diagnosis, severity of illness, or eventual response to treatment. Unipolar depressed patients with environment‐sensitive episodes had lower CSF 5‐HIAA than those with autonomous episodes. Among bipolar depressed patients, those with autonomous episodes had elevated excretion of O‐methylated catecholamine metabolites and of epinephrine, while those with environment‐sensitive episodes had normal excretion of cate‐cholamines and metabolites. Manic subjects with environment‐sensitive episodes had elevated norepinephrine excretion, while this was normal in manics with autonomous episodes. Relationships between environmental sensitivity of affective episodes and neurotransmitter function therefore appear to be related to the type of episode.;

Erectile dysfunction associated with pharmacological agents

The purpose of this chapter is to review pharmacological effects on male erectile dysfunction. As will be documented in this chapter, a wide variety of pharmacological agents have been reported to have sexual side effects. Drugs may influence male sexual function at various levels including (1) sexual interest or desire (also termed libido), (2) the capacity to achieve and maintain an erection sufficient for coitus, (3) ejaculation, and (4) fertility. Although the issue of fertility is beyond the scope of this review, drugs that inhibit fertility often suppress hormonal secretions and may thus influence sexual behavior. This text is concerned primarly with erectile function. However, libido and ejaculation problems often coexist and interact with erectile problems. The effects of drugs on these sexual activities will also be reviewed.

Allopurinol for mania: a randomized trial of allopurinol versus placebo as add-on treatment to mood stabilizers and/or antipsychotic agents in manic patients with bipolar disorder

OBJECTIVE An emerging body of evidence supports a role for dysfunctional purinergic neurotransmission in mood disorders. Adenosine agonists have been shown to have properties similar to those of dopamine antagonists; there is a well-characterized interaction between adenosine and dopamine receptors in the ventral striatum, and increasing adenosinergic transmission has been demonstrated to reduce the affinity of dopamine agonists for dopamine receptors. Allopurinol increases adenosine levels in the brain, and hence is hypothesized to reduce the symptoms of mania. Two randomized, placebo-controlled trials administering add-on allopurinol to manic patients showed significantly greater improvements in Young Mania Rating Scale (YMRS) scores for drug compared to placebo, while a more recent, relatively small, add-on study showed negative results. Based on these data, our objective was to examine the efficacy of allopurinol as add-on treatment to mood stabilizers and/or antipsychotic agents in manic patients with bipolar disorder. METHODS We performed a large, well-powered, multicenter, six-week, randomized, placebo-controlled trial of allopurinol added to mood stabilizers and/or antipsychotic agents in 180 patients with bipolar disorder in an acute manic episode. RESULTS Both groups showed improvement on the YMRS (effect size of 1.5 for placebo and 1.6 for allopurinol), with no difference observed between groups on YMRS scores (t = 0.28, p = 0.78). There was no difference in the proportion of patients who responded to treatment (defined as showing at least 50% improvement in YMRS score) between the two groups (p = 0.92), or in dropout rates (p = 0.84). LIMITATIONS None of our patients received lithium. However, the side effects of lithium and its narrow therapeutic index made the use of lithium less common and, therefore, our study results reflect common current clinical practice. In the present study, we used a variety of antipsychotic and/or mood stabilizing treatments, to which we added allopurinol; one might hypothesize that add-on allopurinol has a different effect in combination with different antipsychotic agents or mood stabilizers. CONCLUSIONS The findings of this large, well-powered study do not support add-on allopurinol as a treatment for acute mania. This study did not test the efficacy of allopurinol as monotherapy.

A randomized controlled trial of allopurinol vs. placebo added on to antipsychotics in patients with schizophrenia or schizoaffective disorder

Adenosine agonists produce behavioral effects similar to dopamine antagonists, hence increasing adenosine levels might improve symptoms of schizophrenia. This hypothesis is supported by three single-site studies indicating that allopurinol, which increases adenosine levels, improved symptoms in patients with schizophrenia. We performed a multi-center, 8-week RCT of allopurinol vs. placebo added to anti-psychotic medications in 248 patients with schizophrenia or schizoaffective disorder. Both groups showed improvement in the PANSS (effect size 1.13) and in clinical and cognitive measures. No difference was observed between groups in primary (t=0.01, p=0.992) or secondary outcome measures. These findings do not support allopurinol as a treatment for schizophrenia.

Pharmacological effects of methylphenidate on plasma homovanillic acid and growth hormone

The acute pharmacological actions of methylphenidate, a potent psychotogenic stimulant, were studied by measuring plasma homovanillic acid (HVA) and serum growth hormone (GH) as indices of presynaptic and postsynaptic functions, respectively. Twenty psychiatric inpatients participated in a double-blind, placebo-randomized study of methylphenidate infusion. Multiple samples of plasma HVA and GH were measured before and up to 24 hours after both methylphenidate and placebo infusions. There was a robust and significant GH response during the 2-hour postmethylphenidate period when compared to placebo. The peak response was significantly greater in male patients than in female patients. Although there were no changes in plasma HVA during the 2 hours following the infusion, there was a significant decrease in HVA 24 hours after methylphenidate as compared to preinfusion baseline values. Plasma HVA values also tended to be lower 24 hours after methylphenidate when compared to the corresponding postplacebo value. Schizophrenic patients did not differ significantly from nonschizophrenic patients in their physiological or biochemical responses.