Subsequent Treatment Response Research Articles

The Treatment of Relapsed Refractory Chronic Lymphocytic Leukemia

Despite the widespread use of highly effective chemoimmunotherapy (CIT), fludarabine-refractory chronic lymphocytic leukemia (CLL) remains a challenging clinical problem associated with poor overall survival (OS). The traditional definition, which includes those patients with no response or relapse within 6 months of fludarabine, is evolving with the recognition that even patients with longer remissions of up to several years after CIT have poor subsequent treatment response and survival. Approved therapeutic options for these patients remain limited, and the goal of therapy for physically fit patients is often to achieve adequate cytoreduction to proceed to allogeneic stem cell transplantation (alloSCT). Fortunately, several novel targeted therapeutics in clinical trials hold promise of significant benefit for this patient population. This review discusses the activity of available and novel therapeutics in fludarabine-refractory or fludarabine-resistant CLL as well as recently updated data on alloSCT in CLL.

Neural correlates of emotional processing in depression: Changes with cognitive behavioral therapy and predictors of treatment response

Major depressive disorder (MDD) is characterized by the presence of disturbances in emotional processing. However, the neural correlates of these alterations, and how they may be affected by therapeutic interventions, remain unclear. The present study addressed these issues in a preliminary investigation using functional magnetic resonance imaging (fMRI) to examine neural responses to positive, negative, and neutral pictures in unmedicated MDD patients ( N = 22) versus controls ( N = 14). After this initial scan, MDD patients were treated with cognitive behavioral therapy (CBT) and scanned again after treatment. Within regions that showed pre-treatment differences between patients and controls, we tested the association between pre-treatment activity and subsequent treatment response as well as activity changes from pre- to post-treatment. This study yielded three main findings. First, prior to treatment and relative to controls, patients exhibited overall reduced activity in the ventromedial prefrontal cortex (PFC), diminished discrimination between emotional and neutral items in the amygdala, caudate, and hippocampus, and enhanced responses to negative versus positive stimuli in the left anterior temporal lobe (ATL) and right dorsolateral PFC. Second, CBT-related symptom improvement in MDD patients was predicted by increased activity at baseline in ventromedial PFC as well as the valence effects in the ATL and dorsolateral PFC. Third, from pre- to post-treatment, MDD patients exhibited overall increases in ventromedial PFC activation, enhanced arousal responses in the amygdala, caudate, and hippocampus, and a reversal of valence effects in the ATL. The study was limited by the relatively small sample that was able to complete both scan sessions, as well as an inability to determine the influence of comorbid disorders within the current sample. Nevertheless, components of the neural networks corresponding to emotion processing disturbances in MDD appear to resolve following treatment and are predictive of treatment response, possibly reflecting improvements in emotion regulation processes in response to CBT.

Rationale for, Barriers to, and Appropriate Medication for the Long-Term Treatment of Depression

Antidepressants have proven efficacy in the treatment of acute depressive episodes and the prevention of relapse over the long-term. However, whether due to ignorance about the chronicity of depression, intolerable adverse effects, or an inappropriate fear of dependence, antidepressants are often discontinued after remission or recovery from an acute episode, which frequently leads to relapse or recurrence. This, in turn, increases the risk of subsequent poor treatment response and lifelong depressive chronicity. Clinicians should focus on preventing depressive relapse with long-term antidepressant pharmacotherapy, thereby improving patients' overall outcomes, particularly with patients at high risk for relapse. When patients with depression have comorbid anxiety, benzodiazepines may be useful but should be used only as short-term augmentation during the beginning phase of antidepressant treatment; long-term treatment of comorbid anxiety is better managed by antidepressants that also treat anxiety disorders.

Ultrasensitive Detection of Minor Drug-Resistant Variants for HIV After Nevirapine Exposure Using Allele-Specific PCR: Clinical Significance

HIV-1 drug resistance mutations have been detected at low frequencies after single-dose nevirapine (sdNVP) for prevention of mother-to-child transmission (PMTCT). We investigated the relationship between these "minor variant" NVP-resistant viruses and clinical outcome with NVP-containing antiretroviral therapy (ART). An allele-specific quantitative PCR (ASPCR) assay was used to quantify the pre-ART frequency of K103N and Y181C in 26 women who had received sdNVP. The cohort was composed of 7 patients who experienced virologic failure and 19 control patients who maintained virologic suppression on NVP-containing ART; all were negative for resistance by standard genotyping. NVP resistance mutations were found in 17 of 26 (65%) patients using ASPCR. The frequency of NVP-resistant viruses ranged from 0.1% to 4.11%. Receiver operating characteristics (ROC) analysis identified a clinical threshold frequency of 0.19% for the ASPCR assay. Application of this threshold demonstrated minor variant resistance in 6 of 7 patients (86%) who failed treatment compared to 6 of 19 patients (32%) who were successful (OR = 13; 95% CI 1.27-133). ASPCR provides a means of detecting minor variant drug-resistant viruses that may impact subsequent treatment response. These data suggest a clinical role for highly sensitive assays to detect and quantify resistant viruses at low frequencies.

Working memory fMRI activation in cocaine-dependent subjects: Association with treatment response

Functional magnetic resonance imaging (fMRI) studies of early abstinence cocaine users offer information about the state of the brain when most cocaine users seek treatment. This study examined the relationship between pretreatment brain function and subsequent treatment response in 19 treatment-seeking early abstinence cocaine-dependent (CD) subjects. These subjects and 14 non-drug-using control subjects underwent fMRI while performing a working memory task with three levels of difficulty. CD subjects were then randomized to treatment studies. Results showed CD subjects had significantly lower (random effects, corrected for multiple comparisons) brain activation in caudate, putamen, cingulate gyrus, middle and superior frontal gyri, inferior frontal gyrus pars triangularis and pars opercularis, precentral gyrus, and thalamus compared with non-drug-using controls. Within CD subjects, thalamic activation significantly correlated with treatment response. This study shows CD subjects in early abstinence have alterations of brain function in frontal, striatal, and thalamic brain regions known to be part of a circuit associated with motor control, reward, and cognition. Subjects with pretreatment thalamic deactivation showed the poorest treatment response, possibly related to thalamic involvement in mesocortical and mesolimbic dopamine projections.

International Cohort Analysis of the Antiviral Activities of Zidovudine and Tenofovir in the Presence of the K65R Mutation in Reverse Transcriptase

A K65R mutation in HIV-1 reverse transcriptase can occur with the failure of tenofovir-, didanosine-, abacavir-, and, in some cases, stavudine-containing regimens and leads to reduced phenotypic susceptibility to these drugs and hypersusceptibility to zidovudine, but its clinical impact is poorly described. We identified isolates with the K65R mutation within the Stanford Resistance Database and a French cohort for which subsequent treatment and virological response data were available. The partial genotypic susceptibility score (pGSS) was defined as the genotypic susceptibility score (GSS) excluding the salvage regimen's nucleoside reverse transcriptase inhibitor (NRTI) component. A three-part virologic response variable was defined (e.g., complete virologic response, partial virologic response, and no virologic response). Univariate, multivariate, and bootstrap analyses evaluated factors associated with the virologic response, focusing on the contributions of zidovudine and tenofovir. Seventy-one of 130 patients (55%) achieved a complete virologic response (defined as an HIV RNA level of <200 copies/ml). In univariate analyses, pGSS and zidovudine use in the salvage regimen were predictors of the virologic response. In a multivariate analysis, pGSS and zidovudine and tenofovir use were associated with the virologic response. Bootstrap analyses showed similar reductions in HIV RNA levels with zidovudine or tenofovir use (0.5 to 0.9 log(10)). In the presence of K65R, zidovudine and tenofovir are associated with similar reductions in HIV RNA levels. Given its tolerability, tenofovir may be the preferred agent over zidovudine even in the presence of the K65R mutation.

PW01-192 - Development of a valid early improvement threshold to predict response and remission in FES

BackgroundTo test in first-episode schizophrenia (FES) patients whether early treatment improvement accurately predicts subsequent treatment outcome and to develop a valid definition for early improvement.Methods188 first episode schizophrenia inpatients were assessed with the Positive and Negative Syndrome Scale (PANSS) at admission and biweekly until discharge within a randomized, double-blind trial. 93 patients were treated with risperidone, 95 with haloperidol. Response was defined as a 40% improvement in PANSS total score from admission to discharge, remission according to the recently proposed consensus criteria and early improvement as an improvement in the PANSS total subscore after the second week. Receiver operator characteristic (ROC) analyses were used to evaluate predictive validity of early improvement and to find the most reasonable cutoff definition according to specificity and sensitivity. A confidence interval for the optimum cutoff was furthermore estimated.ResultsROC analyses revealed reasonable predictability for response (AUC=0.707) and remission (AUC=0.692) concerning early improvement as a predictor for response/remission. No significant differences were found between the two treatment groups. Early improvement defined as a 46% PANSS total score reduction for response and a PANSS total score reduction of 50% for remission obtained the best results in terms of sensitivity and specificity.ConclusionWe were able to confirm that early improvement is a valid predictor of subsequent treatment response and remission. FES patients should at least improve up to 30% in the PANSS total score at week 2 to achieve treatment response and remission.

Imaging advances in developing new medications for addiction

Brain imaging has provided important insights into the clinical neurobiology of addiction for more than 20 years, beginning with the pioneering Positron Emission Tomography (PET) studies of Volkow et al (1988), and continuing to recent studies showing that cocaine addiction is associated with changes in dopamine function that are predictive of choice to self-administer cocaine (Martinez et al, 2007). However, because of their cost and radiation hazards, PET studies of addicted subjects who are undergoing clinical trials have been limited. Although BOLD fMRI has some disadvantages, such as lack of an absolute measure of blood flow or neuronal activity, it has the advantages of repeatability, cost, and safety over PET. One area in which fMRI has shown promise in medication development for addiction is as a predictor of treatment response in clinical trials. Recently, Brewer et al (2008) showed that fMRI brain activation during performance of a Stroop task in cocaine-dependent subjects before treatment was predictive of subsequent treatment response. Other studies are underway in several centers using fMRI as a baseline predictor of treatment response in clinical trials for cocaine dependence, which should provide important information about the neurobiology of medication response in addiction. A second area that shows promise for fMRI in medication development for addictions is in the study of acute effects of medications on brain function in addicted individuals. The use of fMRI in this manner, also termed pharmacoMRI or phMRI, has potential as a tool to drive medication development by providing additional information about the effects of medications before their use in costly, time-consuming phase II clinical trials (Wise and Tracey, 2006). The rationale for using phMRI in medication development for addictions is based on the following: (1) behavioral research has shown that addicted individuals show differences in behavioral performance in tasks such as cue reactivity and behavioral inhibition compared with non-addicted subjects; (2) fMRI of addicted subjects while performing these tasks has shown patterns of brain activation that differ from non-addicted subjects; (3) acute effects of novel compounds on brain activation patterns in addicted subjects while performing these tasks could provide additional information about the pharmacodynamics, and hence the potential utility of these compounds for treatment of addictions. The potential usefulness of this approach has been shown by a recent study showing that an acute dose of methadone reduced fMRI brain activation associated with heroin-related stimuli in opiate addicts (Langleben et al, 2008); however to date, phMRI has not been routinely used as a tool for medication development for addictions. Basic science advances in understanding addiction raise hope for a future with more effective therapeutic strategies for this chronic, relapsing brain disorder. Yet, the progress of candidate medications on the pathway to patients is slow and of the numerous compounds studied for treatment of addictions, few have reached the FDA approval (Vocci and Elkashef, 2005). Novel brain imaging methods, such as phMRI, offer the potential to provide important information about medications for addictions, which could aid in the development of pharmacotherapies for addictions.

Predictors of treatment response to fluvoxamine in obsessive–compulsive disorder: An fMRI study

Recent neuroimaging studies suggest that the pathophysiology of obsessive–compulsive disorder (OCD) may involve more widely distributed large-scale brain systems, including the parietal, occipital, and cerebellar areas, rather than the conventional orbitofronto-striatal model. We hypothesized that not only orbitofrontal cortex and caudate nucleus activities but also posterior brain regions might be associated with subsequent treatment response to serotonin reuptake inhibitors in OCD. The participants were 17 patients with OCD. Each patient was required to undergo fluvoxamine pharmacotherapy for 12 weeks. Before treatment, fMRI images of the subjects were obtained in the context of a symptom-provocation paradigm. The percentage changes in total Yale-Brown Obsessive–Compulsive Scale (Y-BOCS) scores, from pre- to post-treatment, served as the index of treatment response. Statistical Parametric Mapping was used to identify brain loci where pre-treatment brain activation significantly correlated with the subsequent treatment response. Fifteen of 17 patients completed the 12-week treatment. During the symptom provocation task, patients showed brain activation in the left superior temporal gyrus (STG), left precuneus, left frontal cortices, right cerebellum, and right frontal cortices. We found that pre-treatment activation in the right cerebellum ( Z-score = 5.10, x , y , z = 22 , - 84 , - 18 ) and the left STG ( Z-score = 4.95, x , y , z = - 62 , - 22 , 0 ) was positively correlated with the improvement in the Y-BOCS score. Our results suggest that pre-treatment activation in the right cerebellum and in the left STG predict subsequent reduction in OCD symptom severity. There is every possibility that fMRI can be used as a tool to predict treatment response.

Early improvement as a predictor of remission and response in schizophrenia: Results from a naturalistic study

Objective To examine the predictive validity of early improvement in a naturalistic sample of inpatients and to identify the criterion that best defines early improvement. Methods Two hundred and forty-seven inpatients who fulfilled ICD-10 criteria for schizophrenia were assessed with the Positive And Negative Syndrome Scale (PANSS) at admission and at biweekly intervals until discharge from hospital. Remission was defined according to the recently proposed consensus criteria, response as a reduction of at least 40% in the PANNS total score from admission to discharge. Results Receiver operating characteristic (ROC) analyses showed that early improvement (reduction of the PANSS total score within the first 2 weeks of treatment) predicts remission (AUC = 0.659) and response (AUC = 0.737) at discharge. A 20% reduction in the PANSS total score within the first 2 weeks was the most accurate cut-off for the prediction of remission (total accuracy: 65%; sensitivity: 53%; specificity: 76%), and a 30% reduction the most accurate cut-off for the prediction of response (total accuracy: 76%; sensitivity: 47%; specificity: 90%). Conclusion The findings of clinical drug trials that early improvement is a predictor of subsequent treatment response were replicated in a naturalistic sample. Further studies should examine whether patients without early improvement benefit from an early change of antipsychotic medication.

The value of HMPAO SPECT in predicting treatment response to citalopram in patients with major depression

Alterations of regional cerebral blood flow (rCBF) in prefrontal cortex and the anterior cingulate cortex are conspicuous imaging findings in patients with major depression (MD). While these rCBF changes have been suggested as functional disease markers, data in large patient samples examining treatment response prediction to antidepressant therapy are limited. This study examined the predictive value of Tc-99m-HMPAO-SPECT for subsequent treatment response to antidepressant therapy with citalopram in an unprecedented large collective of patients. Ninety-three patients with MD were examined with Tc-99m-HMPAO-SPECT twice, at the beginning of citalopram-treatment (T1) and after 4 weeks of treatment (T2). To determine the impact of rCBF changes associated with treatment response, the patient sample was divided into two subgroups: responders (44 patients) and non-responders (49 patients). A two-sample t-test was used to determine group-specific rCBF-differences. Age, gender and initial Hamilton Rating Scale for Depression (HRSD) were treated as regressors of no interest. The responder group revealed significant relative rCBF increases at T1 in a large region en-compassing predominantly prefrontal and temporal cortices as well as subgenual cingulate cortex. No relative rCBF decreases were detected in this group. The comparison between T1 and T2 revealed trends of rCBF decreases in inferior frontal gyrus and rCBF increases in premotor cortex in the responder group. Our data show that rCBF measurements with TC-99M-HMPAO-SPECT provide a predictor estimate for subsequent treatment response in depressed patients undergoing antidepressant therapy with citalopram. This effect is highly significant and, most notably, independent of the initial HRSD score.

Prospective study of bone mineral density and metabolism in patients with chronic hepatitis C during pegylated interferon α and ribavirin therapy

The importance of osteoporosis as a complication of end-stage liver disease is well known. However, significant osteopenia may occur in earlier stages of chronic hepatitis C (CHC). Furthermore, antiviral therapy may influence bone metabolism. Thirty patients with CHC genotype 1 infection and without established cirrhosis were treated with peginterferon-alfa and ribavirin. Dual-energy x-ray absorptiometry was performed at baseline, after 48 weeks of therapy, and by the end of a 24-week follow-up period. Bone mineral density (BMD), T-scores, and Z-scores were assessed. Serum C-terminal propeptide of type I collagen (CICP) and osteocalcin levels were measured. Thirteen patients had osteopenia (43%) and osteoporosis was present in four patients (13%). Antiviral therapy led to significant on-treatment increases of lumbar spine and hip BMD (P < or = 0.05) as well as T-scores (P < or = 0.05) and Z-scores (P < or = 0.01) irrespective of subsequent treatment response. Further analyses showed that in patients with sustained virological response (n = 19) most parameters remained highly above baseline values by the end of the 24-week follow-up period, while patients with virological relapse (n = 11) had decreases of BMD, T-scores and Z-scores thereafter that did not differ from baseline. Serum CICP and osteocalcin levels decreased during therapy. Osteocalcin levels remained below baseline in sustained responder, but showed an increase in relapsers by the end of the 24-week follow-up (P < or = 0.05). Osteopenia is detectable in a substantial proportion of CHC patients without established cirrhosis. Antiviral therapy leads to an on-treatment increase of BMD, which may last in those patients who achieve a sustained virological response.

Treatment Options for Proliferative Lupus Nephritis

Systemic lupus erythematosus involves the kidney in up to 60% of patients, and if untreated, may result in complete loss of kidney function. In this article, we review meta-analyses and clinical trial data on the therapeutic options for proliferative lupus nephritis, and complete a meta-analysis of the use of mycophenolate mofetil (MMF) compared with cyclophosphamide-based regimens. Clinical trials have found that cyclophosphamide-based regimens result in a decreased risk of end-stage renal disease, but are associated with significant toxicity in lupus nephritis. Even though the survival advantage of the US National Institutes of Health and Euro-Lupus regimens based on intravenous and oral cyclophosphamide has not been established, these approaches are broadly adopted in proliferative lupus nephritis. Recent studies have confirmed the therapeutic equivalence and potential comparative superiority of MMF and cyclophosphamide in induction of remission in patients with lupus nephritis. Use of MMF resulted in a lower incidence of infection and loss of gonadal function compared with cyclophosphamide regimens. Cyclophosphamide plus corticosteroids could represent the induction agents of choice in patients with severe lupus nephritis, whereas MMF could be used as an induction agent in patients with mild disease, patients who wish to preserve fertility and those at high risk of infections. However, given the complexity of disease activity in patients with lupus nephritis, the initial treatment options need to be individualized and altered based on the subsequent treatment response. Ongoing clinical trials will provide further evidence.

Hepatic gene expression during treatment with peginterferon and ribavirin: Identifying molecular pathways for treatment response

The reasons for hepatitis C treatment failure remain unknown but may be related to different host responses to therapy. In this study, we compared hepatic gene expression in patients prior to and during peginterferon and ribavirin therapy. In the on-treatment group, patients received either ribavirin for 72 hours prior to peginterferon alpha-2a injection or peginterferon alpha-2a for 24 hours, prior to biopsy. The patients were grouped into rapid responders (RRs) with a greater than 2-log drop and slow responders (SRs) with a less than 2-log drop in hepatitis C virus RNA by week 4. Pretreatment biopsy specimens were obtained from a matched control group. The pretreatment patients were grouped as RRs or SRs on the basis of the subsequent treatment response. Gene expression profiling was performed with Affymetrix microarray technology. Known interferon-stimulated genes (ISGs) were induced in treated patients. In the pretreatment group, future SRs had higher pretreatment ISG expression than RRs. On treatment, RRs and SRs had similar absolute ISG expression, but when it was corrected for the baseline expression with the pretreatment group, RRs showed a greater fold change in ISGs, whereas SRs showed a greater change in interferon (IFN)-inhibitory pathways. The patients pretreated with ribavirin had heightened induction of IFN-related genes and down-regulation of genes involved in IFN inhibition and hepatic stellate cell activation. These data suggest that ISG inducibility is important for the treatment response and that ribavirin may improve outcomes by enhancing hepatic gene responses to peginterferon. Collectively, these mechanisms may provide a molecular basis for the improved efficacy of combination therapy.

Increased Anterior Cingulate/Medial Prefrontal Cortical Glutamate and Creatine in Bipolar Depression

Proton magnetic resonance spectroscopy ((1)HMRS) is an in vivo brain imaging method that can be used to investigate psychotropic drug mechanism of action. This study evaluated baseline (1)HMRS spectra of bipolar depressed patients and whether the level of cerebral metabolites changed after an open trial of lamotrigine, an anti-glutamatergic mood stabilizer. Twenty-three bipolar depressed and 12 control subjects underwent a MRS scan of the anterior cingulate/medial prefrontal cortex. The scan was performed on a GE whole-body 1.5 T MRI scanner using single-voxel PRESS (TE/TR=30/3000 ms, 3 x 3 x 3 cm(3) and post-processed offline with LCModel. Baseline CSF-corrected absolute concentrations of glutamate+glutamine ([Glx]), glutamate ([Glu]), and creatine+phosphocreatine ([Cr]) were significantly higher in bipolar depressed subjects vs healthy controls. The non-melancholic subtype had significantly higher baseline [Glx] and [Glu] levels than the melancholic subtype. Remission with lamotrigine was associated with significantly lower post-treatment glutamine ([Gln]) in comparison to non-remission. These data suggest that non-melancholic bipolar depression is characterized by increased glutamate coupled with increased energy expenditure. Lamotrigine appears to reduce glutamine levels associated with treatment remission. Further study is encouraged to determine if these MR spectroscopic markers can delineate drug mechanism of action and subsequent treatment response.

Predictors of Fluvoxamine Response in Contamination-related Obsessive Compulsive Disorder: A PET Symptom Provocation Study

The purpose of this study was to identify neuroimaging predictors of medication response in contamination-related obsessive compulsive disorder (OCD). Prior studies of OCD had indicated that glucose metabolic rates within orbitofrontal cortex (OFC) were inversely correlated with subsequent response to serotonergic reuptake inhibitors (SRIs) and that glucose metabolic rates within posterior cingulate cortex (PCC) were positively correlated with subsequent response to cingulotomy. Nine subjects with contamination-related OCD underwent a 12-week open trial of treatment with the SRI fluvoxamine. Percent change in Yale-Brown Obsessive Compulsive Scale score, from pre- to post-treatment, served as the index of treatment response. Positron emission tomography (PET) measurements of regional cerebral blood flow (rCBF) were obtained prior to treatment, in the context of a symptom provocation paradigm. Statistical parametric mapping was used to identify brain loci where pre-treatment rCBF was significantly correlated with subsequent treatment response. Consistent with a priori hypotheses, lower rCBF values in OFC and higher rCBF values in PCC predicted better treatment response. This same pattern of associations was present regardless of whether the imaging data were acquired during a provoked or neutral state. These findings are consistent with prior studies of OCD, indicating that PET indices of brain activity within OFC are inversely correlated with subsequent response to SRIs. In addition, similar to findings regarding cingulotomy for OCD, indices of activity within PCC appear to be positively correlated with response to fluvoxamine as well. Finally, this pattern is sufficiently robust as to be relatively independent of symptomatic state at the time of tracer uptake.

Monoamine Neurotransmitter Interactions in Drug-Free and Neuroleptic-Treated Schizophrenics

To study recent suggestions by a number of investigators that interactions between monoamine neurotransmitter systems play an important role in schizophrenia. It has not been clear how hypotheses about interactions might be tested in clinical data. One means for indexing interactions between monoamine neurotransmitter systems may be to compare correlations between cerebrospinal fluid (CSF) monoamine metabolite (homovanillic acid [HVA], 5-hydroxyindoleacetic acid [5-HIAA], and 3-methoxy-4-hydroxyphenylglycol [MHPG]) or ratios of these metabolites (HVA/5-HIAA and HVA/MHPG). We compared these putative measures of monoamine neurotransmitter interaction in 50 drug-free patients with schizophrenia (hospitalized on an inpatient ward of a tertiary care hospital) and 33 normal controls and examined the effects of neuroleptic antipsychotic treatment on these measures in 41 patients (22 of whom had antecedent drug-free CSF data). Drug-free patients with schizophrenia had significantly smaller correlations between CSF monoamine metabolites than normal controls. Longer drug-free time was associated with even smaller correlations between metabolites, suggesting that the difference between controls and patients was not due to acute drug withdrawal. After treatment with neuroleptic antipsychotics there were significant increases in the HVA/5-HIAA and HVA/MHPG ratios, as well as increases in correlations between monoamine metabolites. After treatment, there were no significant differences in metabolite correlations between patients and controls. Metabolite ratios and correlations did not predict subsequent treatment response, but preliminary analyses demonstrated negative relationships between HVA/5-HIAA and HVA/MHPG ratios and Brief Psychiatric Rating Scale rating at that time. The present findings are consistent with and support hypotheses suggesting that interactions between monoamine systems are altered in schizophrenia and that antipsychotic treatment may affect the functional balance between different monoamine neurotransmitters (although one should keep in mind factors other than interactions between monoamine systems that affect metabolite correlations and ratios.

Effects of smoking on serum lipoproteins and bone mineral content during postmenopausal hormone replacement therapy

We examined the effect of smoking on the treatment response in serum estrogens, serum lipids and lipoproteins, and bone mineral content in 110 postmenopausal women treated for 2 years with either percutaneous or orally administered combined hormones or placebo and followed up by examinations every 3 months. Serum estradiol and estrone levels during oral hormone administration were lower in smokers than in nonsmokers, whereas no differences related to smoking habits were observed during percutaneous hormone administration. Serum total and low-density lipoprotein cholesterol were significantly reduced in both smokers and nonsmokers receiving hormones, but the response in smokers was only half that observed in nonsmokers (not significant). When the impact of the route of hormone administration was examined in relation to smoking habits, the response in serum total and low-density lipoprotein cholesterol in smokers receiving oral hormones was significantly lower (p less than 0.05) than that observed in nonsmokers. No differences in serum lipids or lipoproteins were observed between smokers and nonsmokers receiving percutaneous hormones. The response in bone mineral content in smokers and nonsmokers receiving percutaneous hormones and placebo was not significantly different, although the overall response differed significantly in the two groups (p less than 0.001). In contrast, the response in smokers receiving oral hormones was significantly lower than that observed in the corresponding nonsmokers (p less than 0.01). We conclude that smoking greatly affects the response on circulating levels of estrogens in postmenopausal women treated with orally administered hormone replacement therapy and that the subsequent treatment response on serum lipids and lipoproteins and on bone mineral content is reduced accordingly. The study suggests that alternative routes of administration should be considered when postmenopausal estrogen therapy is instituted in women who smoke.

Intravenous hexamethonium sensitivity and responses to oral treatment.

This study represents an effort to distinguish between neurogenic and humoral vasoconstrictive factors in a representative group of hypertensive patients by the response to hexamethonium ganglionic blockade. The correlation between intravenous hexamethonium sensitivity and subsequent treatment response was also determined.