MHPG and heart rate as correlates of nonresponse to drug therapy in panic disorder patients A preliminary report

Little is known about biological predictors of treatment response in panic disorder (PD). In the present study heart rate, blood pressure, plasma cortisol and plasma MHPG were investigated at baseline in a sample of 44 PD patients as possible predictors for nonresponse to treatment. We used a strict definition of nonresponse to find patients who did not respond at all after 12 weeks of treatment with brofaromine or fluvoxamine. Patients were considered nonresponders when they fulfilled two criteria: they did not show a 50% reduction of agoraphobic avoidance and they still experienced panic attacks at endpoint. The variables that differed significantly between the groups were used to predict nonresponse to drug therapy. Using this strict definition of nonresponse, 15 patients (32.6%) were considered nonresponders. These patients were characterised by a higher plasma MHPG concentration and a higher heart rate at baseline. These variables were subsequently used to predict nonresponse. Received: 29 December 1995 /Final version: 16 May 1996     

Heart rate variability as predictor of nonresponse to mirtazapine in panic disorder: a preliminary study

Using spectral analysis of heart rate, several studies have shown that panic disorder patients are characterized by a reduced heart rate variability (HRV), indicative of abnormalities in autonomous nervous system (ANS) function. We recently reported that patients with panic disorder, who did not respond to pharmacotherapy, were characterized at baseline by a higher heart rate. In this study, ANS functioning is investigated as a possible predictor of nonresponse to pharmacotherapy. Twenty-eight medication-free panic disorder patients entered a 12-week open-label treatment study with mirtazapine. Five-minute HRV recordings were obtained before treatment and were analysed using spectral analysis. The data of 17 patients could be used. The total spectrum and low frequency power of responders to mirtazapine were significantly higher than those of nonresponders. Our findings suggest that nonresponders to short-term mirtazapine treatment are characterized at baseline by a lowered output of the ANS. The results are preliminary in view of the small sample studied.     

Urinary 3-methoxy-4-hydroxyphenylglycol and the depression-type score as predictors of differential responses to antidepressants.

Pretreatment 24 hr urinary 3-methoxy-4-hydroxyphenylglycol (MHPG) levels and the Depression-type (D-type) scores (derived from a multivariate discriminant function equation based on levels of urinary catecholamines and metabolites) were examined as possible predictors of antidepressant responses to either imipramine or alprazolam. In the case of imipramine, the responders had significantly lower pretreatment urinary MHPG levels (p = 0.002) and D-type scores (p less than 0.001) than did nonresponders. In contrast, responders to the antidepressant effects of alprazolam had significantly higher pretreatment urinary MHPG levels (p less than 0.05) and D-type scores (p = 0.02) than did nonresponders. For each antidepressant treatment, D-type scores appeared to provide a better separation of responders from nonresponders than did urinary MHPG levels. For each drug, the effect size for the difference in mean log-transformed D-type scores between responders and nonresponders was greater than the effect size for the difference in mean log-transformed MHPG levels. The difference between the effect sizes was statistically significant for imipramine (p = 0.02) and tended toward significance for alprazolam using two-tailed tests. These results suggest that the D-type equation, which was initially derived to separate bipolar manic-depressive depressions from other subgroups of depressive disorders, can also be used to predict differential responses to certain antidepressant drugs in patients with unipolar depressions.     

Imipramine in panic disorder. 2. Effects on α2-adrenoceptor function

Untreated patients with panic disorder have been shown to have altered α(2)-adrenoceptor sensitivity, as assessed by clonidine challenge testing. We investigated clonidine-induced biochemical, physiological, hor monal and psychological responses in six panic patients, before and after treatment with imipramine. Comparison of the clonidine-induced fall in plasma MHPG pre- and post-treatment showed it to be sig nificantly reduced after imipramine. Significantly smaller clonidine-induced falls in diastolic blood pressure and heart rate occurred after imipramine treatment. However, growth hormone and sedation responses were not altered. These data suggest that reduced sensitivity of some central α(2)-adrenoceptors occurs during treatment of panic disorder with imipramine. However, these changes do not fully explain the therapeutic actions of antidepressants in this condition.     

Epinephrine and fear of bodily sensations in panic disorder and social phobia

Fear of bodily symptoms of arousal has been implicated in the pathogenesis of both spontaneously occurring and experimentally provoked panic. Fear of bodily symptoms may be characteristic for panic disorder (PD) and is hypothesized to predict state anxiety and panic frequency during experimentally induced peripheral arousal. Twenty-eight subjects, 14 with PD and 14 with social phobia (SP) were infused with placebo and epinephrine (20, 40 and 80 ng/kg bodyweight/min) according to a fixed schedule in a single blind design. Fear of bodily symptoms was higher in subjects with PD, who also reported more bodily symptoms and higher state anxiety scores during the experiment. The panic rate (five out of 14), however, was the same in both groups. Panickers did not differ from non-panickers in trait- or baseline measures except for fear of bodily symptoms, which was marginally higher in panickers. Panickers showed greater reactivity in heart rate, diastolic blood pressure and capillary PCO(2). Our data do not support the hypothesis of a major role for fear of bodily symptoms in epinephrine-induced panic. Also, our results do not demonstrate a different reaction to epinephrine in PD and SP with situational panic attacks.     

丙种球蛋白无反应型川崎病的预测指标

目的：寻找能预测川崎病患儿对丙种球蛋白（简称丙球,IVIG）治疗无反应的生物学指标.方法：回顾性分析310例IVIG治疗敏感及IVIG治疗无反应的川崎病患儿的病例资料.采用单因素方差分析,使用曲线下面积获得这些因素的临界值.对单因素分析结果提示与IVIG无反应有显著相关的因素,进行多元Logistic逐步回归分析.结果：在这310名患儿中,IVIG无反应型的有30例（占9.7％）,这部分患儿C反应蛋白、白细胞、中性粒细胞比值、谷草转氨酶、谷丙转氨酶、总胆红素和氨基末端脑钠肽前体高于对IVIG敏感的川崎病患儿.与川崎病对IVIG敏感的患儿相比,川崎病IVIG无反应型患儿血钠、高密度脂蛋白水平更低.结论：通过多元logistic回归分析证实,ALT≥84 IU/L,总胆红素≥15.39 μmmol/L是丙球无反应型川崎病的两个独立的预测因子.因此,ALT以及总胆红素水平升高可能是丙球无反应型川崎病患儿的有用的预测指标.     

Acute and chronic idazoxan in normal volunteers: biochemical, physiological and psychological effects

The acute and chronic effects of the selective a(2)-antagonist idazoxan were studied in 12 normal volunteers. Plasma 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), blood pressure and psychological responses to oral challenge doses of idazoxan 40 mg were measured twice, on the first and 22nd day of treatment with idazoxan 40 mg t.d.s. Changes in nocturnal melatonin output were studied on six occasions, before, during and after idazoxan treatment. Although baseline MHPG levels were significantly reduced after chronic treatment with idazoxan, idazoxan challenge did not alter MHPG concentrations on either test day. A small rise in systolic blood pressure occurred after acute but not chronic idazoxan challenge tests. Systolic blood pressure values were significantly lower during the chronic compared with the acute test. Diastolic blood pressure and heart rate were not affected by acute or chronic treatment. Subjects reported increases in self- ratings of arousal and reductions in sedation and anxiety of similar magnitude after acute and chronic idazoxan. Nocturnal plasma melatonin secretion was not altered by drug administration or withdrawal, although urinary 6-sulphatoxymelatonin excretion was significantly reduced on acute withdrawal. The increase in systolic blood pressure and arousal self-ratings after acute idazoxan are in accordance with the reported effects of other a(2)-antagonists, although we did not find increased anxiety or elevated plasma MHPG levels. Chronic idazoxan appears to reduce or normalize activity of noradrenergic systems, indicated by reduced baseline systolic blood pressure and MHPG, and loss of the pressor response to idazoxan. Withdrawal of idazoxan leads to an abrupt fall in noradrenergic activity, as demonstrated by the fall in urinary 6-sulphatoxymelatonin.     

S100B Serum Levels Predict Treatment Response in Patients with Melancholic Depression

Background:

There is an ongoing search for biomarkers in psychiatry, for example, as diagnostic tools or predictors of treatment response. The neurotrophic factor S100 calcium binding protein B (S100B) has been discussed as a possible predictor of antidepressant response in patients with major depression, but also as a possible biomarker of an acute depressive state. The aim of the present study was to study the association of serum S100B levels with antidepressant treatment response and depression severity in melancholically depressed inpatients.

Methods:

After a wash-out period of 1 week, 40 inpatients with melancholic depression were treated with either venlafaxine or imipramine. S100B levels and Hamilton Depression Rating Scale (HAM-D) scores were assessed at baseline, after 7 weeks of treatment, and after 6 months.

Results:

Patients with high S100B levels at baseline showed a markedly better treatment response defined as relative reduction in HAM-D scores than those with low baseline S100B levels after 7 weeks (P=.002) and 6 months (P=.003). In linear regression models, S100B was a significant predictor for treatment response at both time points. It is of interest to note that nonresponders were detected with a predictive value of 85% and a false negative rate of 7.5%. S100B levels were not associated with depression severity and did not change with clinical improvement.

Conclusions:

Low S100B levels predict nonresponse to venlafaxine and imipramine with high precision. Future studies have to show which treatments are effective in patients with low levels of S100B so that this biomarker will help to reduce patients’ burden of nonresponding to frequently used antidepressants.     

Effects of acute paroxetine treatment on the consumption of cigarette smoking and caffeine in depressed patients

In the present study, we examined the effects of acute treatment with paroxetine on the consumption of cigarette smoking and caffeine in 65 patients who met the DSM-IV criteria for major depressive disorder (M/F: 28/37, age: 48 +/- 15 years). Plasma levels of cotinine or caffeine were analysed using high-performance liquid chromatography (HPLC). The amount of cigarette smoking and plasma levels of cotinine, but not caffeine, decreased 4 weeks after paroxetine treatment. There was no difference between smokers and nonsmokers with respect to their response to paroxetine treatment. In addition, plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) levels in responders to paroxetine treatment was higher than those in nonresponders, and there was a negative correlation between the changes in plasma MHPG levels and the changes in Hamilton rating scale for depression (Ham-D) scores before and 4 weeks after paroxetine administration. These results suggest that paroxetine has the potential to reduce the amount of cigarette smoking in depressed smokers, and we reconfirmed our previous results that depressed patients with higher plasma MHPG levels had better response to paroxetine treatment than those with lower plasma MHPG levels using larger depressed samples.     

Baseline prediction of 7-month cocaine abstinence for cocaine dependence patients

A broad range of baseline subject variables was evaluated to identify predictors of 7-month cocaine use for 160 lower socioeconomic cocaine dependent male veteran patients participating in either an intensive 1-month day hospital (DH; n=90) or a 1-month inpatient (INP; n=70) treatment program. The baseline measures included sociodemographic variables, the seven Addiction Severity Index composite scores, cocaine urine toxicology, craving, the SCL-90 total score, and lifetime psychiatric diagnoses. Since a proportion of subjects who reported no use at follow-up had positive urines, both liberal and conservative data estimation strategies were employed for subjects without urine toxicology data at follow-up who had reported no use (21% of subjects). Analyses were done separately for the DH and INP subjects. Under the conservative definition of cocaine abstinence/use, univariate correlations of predictor variables with 7-month cocaine use revealed no statistically significant relationships. Under the liberal definition of cocaine abstinence/use, only one variable, greater severity of alcohol problems at intake predicted cocaine abstinence at outcome. Because of the inability to predict treatment success, originally planned logistic regression analyses were not undertaken. The findings point to the difficulty of predicting long-term outcomes in cocaine dependent patients based on baseline information and to the importance of obtaining objective data on cocaine use.     

Increased cerebrospinal fluid levels of endorphin immunoreactivity in panic disorder

Cerebrospinal fluid (CSF) concentrations of beta-endorphin-like immunoreactivity (END-IR) were determined in 11 female and 6 male patients fulfilling the diagnostic criteria of panic disorder (PD) and in matched controls. Eleven of the PD patients had been taking moderate doses of benzodiazepines (BZD) irregularly without satisfactory effect against the panic attacks while six were totally drug-free. No medication was allowed for at least 24 hours before the lumbar puncture. In six patients a second lumbar puncture was performed after 2 to 3 months of treatment with imipramine or clomipramine. In PD patients, CSF levels of END-IR were significantly higher than in controls. Patients that had been taking BZD had somewhat higher concentrations of END-IR than those taking no medication; however, totally drug-free patients also displayed END-IR levels that were significantly higher than in controls. Although they effected a dramatic reduction of the panic attacks, antidepressants did not influence CSF END-IR concentrations.     

Serotonin function in panic disorder: a double blind placebo controlled study with fluvoxamine and ritanserin

In order to evaluate serotonin (5-HT) function in panic disorder, a double blind placebo controlled study was conducted with ritanserin, a specific 5-HT₂ receptor antagonist, and fluvoxamine, a selective 5-HT reuptake inhibitor, in 60 patients with panic disorder. Patients were treated for 8 weeks with 150 mg fluvoxamine, 20 mg ritanserin or placebo; these dose levels were reached after 1 week. In addition, as an index of 5-HT function in panic disorder, plasma concentration of -endorphin, cortisol and 5-hydroxyindolacetic-acid (5-HIAA) were measured. Furthermore, 5-HT uptake in blood platelets was assessed. Noradrenergic function was assessed by measuring plasma MHPG concentration. In addition, plasma melatonin concentration was measured. Treatment with fluvoxamine resulted in a profound reduction in the number of panic attacks, followed by a decrease in avoidance behavior. Treatment with ritanserin appeared to be ineffective. During treatment no significant changes were observed in plasma concentrations of -endorphin, cortisol, 5-HIAA and MHPG. With respect to 5-HT kinetics in blood platelets, a substantial increase in K_m was observed after treatment with fluvoxamine, whereas V_max decreased. After treatment with fluvoxamine, plasma concentration of melatonin was significantly increased, which suggests that melatonin synthesis is in part under serotonergic control. The findings of the present study do not support the hypothesis that 5-HT₂ receptors are supersensitive in patients suffering from panic disorder, but allow no conclusions about the involvement of other 5-HT receptor subtypes.     

Patient predictors of alcohol treatment outcome: a systematic review

Patient characteristics as predictors of alcohol use disorder treatment outcome were examined on three levels, identifying whether or not variables were significant predictors of drinking-related outcome in univariate analysis, in multivariate analysis, and in multivariate analyses limited to studies including several "key predictors." Also, a model was developed to predict total percentage of variance in treatment outcome accounted for in each study using each of the key predictors and a range of methodological factors. The most consistent univariate predictors were baseline alcohol consumption, dependence severity, employment, gender, psychopathology rating, treatment history, neuropsychological functioning, alcohol-related self-efficacy, motivation, socioeconomic status/income, treatment goal, and religion. When these key predictors were combined into multivariate analyses, baseline alcohol consumption and gender showed substantial reductions in predictive consistency whereas the remaining variables were not greatly affected. The most consistent predictors overall were dependence severity, psychopathology ratings, alcohol-related self-efficacy, motivation, and treatment goal. The two predictor variables most associated with greater variance accounted for in predictive models, when controlling for broader methodological variables, were baseline alcohol consumption and dependence severity. Few predictor variables were examined in more than a third of studies reviewed, and few variables were found to be significant predictors in a clear majority of studies. However, a subset of variables was identified, which collectively could be considered to represent a consistent set of predictors. Too few studies controlled for other important predictor variables. Attempts to synthesize findings were often hampered by lack of agreement of the best measure for predictor variables.     

Problem drinkers: evaluation of a stepped-care approach

The present study evaluated a stepped-care model for the treatment of problem drinkers; those not severely dependent on alcohol. The initial treatment consisted of a motivationally based, four-session outpatient treatment. Based on previous research, treatment nonresponders were defined as having consumed more than 12 drinks per week between the assessment and third session. Six-month follow-up interviews were conducted on three groups of problem drinkers: (1) those who responded to the initial intervention (n = 67); (2) those who did not respond to the initial treatment (n = 36); and (3) those who did not respond to the initial treatment and received a supplemental intervention (n = 33). The last two groups were used to evaluate whether providing treatment nonresponders with an additional "step" would improve treatment outcomes. The primary dependent measures were posttreatment percent days abstinent and posttreatment drinks per drinking day. Results suggested that (1) within treatment drinking can help identify treatment nonresponse in stepped-care models; (2) the supplemental intervention did not influence posttreatment drinking; (3) treatment responders and nonresponders sought additional help at the same rate. The present study is the first study on stepped-care for alcohol treatment and provides a methodology for evaluating stepped interventions. Recommendations for future research in this area include more attention to assessing the needs of treatment nonresponders and help seeking behavior of both responders and nonresponders after an initial intervention.     

Clinical pharmacogenetic model to predict response of MTX monotherapy in patients with established rheumatoid arthritis after DMARD failure

Background: The performance of a clinical pharmacogenetic model to predict nonresponse of methotrexate (MTX) monotherapy in patients with established rheumatoid arthritis (RA) and failure of disease-modifying antirheumatic drugs (DMARDs) was studied. Methods: For 75 RA patients receiving MTX monotherapy for 6 months, DNA and clinical data were available. Risk scores for nonresponse at 6 months (disease activity score >2.4), were calculated using the pharmacogenetic prediction model utilizing four clinical factors and four polymorphisms in the genes MTHFD1, AMPD1, ITPA and ATIC. Results: At 6 months, there were 25 responders and 50 nonresponders. Using the clinical pharmacogenetic prediction model, 75% (56 out of 75) were categorized into predicted responders (risk score ≤3.5) and predicted nonresponders (risk score ≥6). At 6 months, the negative predictive value was 81% (21 out of 26) and the positive predictive value was 47% (14 out of 30). Conclusion: The pharmacogenetic model predicts nonresponse to MTX monotherapy, but performs better in DMARD naive recent-onset RA patients than in patients with preceding DMARD failure. Original submitted 17 February 2012; Revision submitted 10 May 2012.     

Single-Subject Anxiety Treatment Outcome Prediction using Functional Neuroimaging

The possibility of individualized treatment prediction has profound implications for the development of personalized interventions for patients with anxiety disorders. Here we utilize random forest classification and pre-treatment functional magnetic resonance imaging (fMRI) data from individuals with generalized anxiety disorder (GAD) and panic disorder (PD) to generate individual subject treatment outcome predictions. Before cognitive behavioral therapy (CBT), 48 adults (25 GAD and 23 PD) reduced (via cognitive reappraisal) or maintained their emotional responses to negative images during fMRI scanning. CBT responder status was predicted using activations from 70 anatomically defined regions. The final random forest model included 10 predictors contributing most to classification accuracy. A similar analysis was conducted using the clinical and demographic variables. Activations in the hippocampus during maintenance and anterior insula, superior temporal, supramarginal, and superior frontal gyri during reappraisal were among the best predictors, with greater activation in responders than non-responders. The final fMRI-based model yielded 79% accuracy, with good sensitivity (0.86), specificity (0.68), and positive and negative likelihood ratios (2.73, 0.20). Clinical and demographic variables yielded poorer accuracy (69%), sensitivity (0.79), specificity (0.53), and likelihood ratios (1.67, 0.39). This is the first use of random forest models to predict treatment outcome from pre-treatment neuroimaging data in psychiatry. Together, random forest models and fMRI can provide single-subject predictions with good test characteristics. Moreover, activation patterns are consistent with the notion that greater activation in cortico-limbic circuitry predicts better CBT response in GAD and PD.     

Covariance of plasma free 3-methoxy-4-hydroxyphenethyleneglycol and diastolic blood pressure

To test the acute effects of clonidine on plasma levels of 3-methoxy-4-hydroxyphenethyleneglycol (MHPG), the major metabolite of brain norepinephrine (NE), and to examine the relationship between plasma MHPG and concurrently measured blood pressure variables, we performed a series of 31 double blind, placebo controlled, test days in which clonidine (1 and 5 μg/kg) or placebo was administered (p.o. at 9:00 a.m.) to six fasting normotensive male subjects. Three h following the 5 μg/kg clonidine dose, plasma MHPG reached a nadir significantly below both baseline and placebo levels (P < 0.05). Mean MHPG concentrations were significantly correlated with diastolic blood pressure (sitting: r = 0.46, df = 88, P < 0.00001; standing r = 0.49, df = 73, P < 0.00001). Unexpectedly, this relationship was independent of clonidine dose and sampling time. Under drug-free conditions, the correlation between plasma free MHPG and diastolic blood pressure remained significant (sitting: r = 0.43, df = 40, P = 0.003; standing: r = 0.46, df = 33, P = 0.006). The findings are considered in light of evidence implicating brain NE systems in the regulation of blood pressure.     

Definition,evaluation, and management of treatment refractory mania

Treatment refractory mania is a common clinical problem. Unfortunately, the treatment of acute mania refractory to standard antimanic and mood-stabilizing medications has not been well studied. This review will discuss the definition, evaluation, and differential diagnosis of treatment refractory mania; the definition of an adequate treatment trial for acute mania; the identification of predictors of treatment response; and clinical trials in treatment refractory mania. Computerized searches of the medical literature regarding treatment refractory mania were undertaken using Paperchase (1966-2001), and bibliographies of all articles identified were reviewed to identify all relevant case reports, case series, clinical trials, and methodologic and phenomenologic reports. Operational definitions of treatment refractory mania were proposed based on sequential nonresponse to adequate trials of antimanic agents. The average time of onset of antimanic agents studied in randomized trials was 1 to 2 weeks. Clinical tools for assessing treatment response retrospectively and prospectively appear to have an important role in managing medication treatment in patients with bipolar disorder. Relatively few reliable predictors of treatment response to established antimanic agents have been identified. However, these predictors represent important factors in treatment selection to minimize the probability of nonresponse. Very few randomized, controlled trials of antimanic agents have been conducted in patients with treatment refractory mania. Field testing of treatment algorithms and systematic collection of data from naturalistic treatment studies should provide much-needed data regarding the efficacy of antimanic agents in treatment refractory mania.     

Aripiprazole and dehydroaripiprazole plasma concentrations and clinical responses in patients with schizophrenia

Aripiprazole is widely used to treat schizophrenia. Plasma levels of aripiprazole and its active metabolite dehydroaripiprazole and their clinical responses in patients were explored. Forty-five (male/female: 19/26) patients with schizophrenia were treated with aripiprazole after a washout period of at least 3 days. There was no concomitant psychotropic except benzodiazepines for insomnia. The Positive and Negative Syndrome Scale (PANSS) was used to measure the clinical response at baseline and at weeks 2, 4, and 6. Blood was drawn at week 6 to measure the plasma concentrations of aripiprazole and dehydroaripiprazole. Patients with a PANSS score that decreased by more than 20% were defined as responders after 6 weeks of treatment. There was no difference in baseline PANSS scores or the daily dosage used between responders (n = 28) and nonresponders (n = 17) (15.0 ± 5.9 vs 12.9 ± 6.9 mg, respectively; P = 0.203). The responders showed a trend toward a higher plasma concentration of aripiprazole than nonresponders (234.4 ± 156.7 vs 163.5 ± 77.2 ng/mL, respectively; P = 0.117) and a significantly higher plasma concentration of dehydroaripiprazole (101.6 ± 58.0 vs 66.0 ± 48.4, respectively; P = 0.023). Higher plasma concentrations of aripiprazole and its active metabolite dehydroaripiprazole were noted in responders than nonresponders. Compared with Western patients, Oriental patients had higher plasma concentrations of aripiprazole and dehydroaripiprazole at the same dose. We suggest that therapeutic drug monitoring of aripiprazole will help improve the response in clinical practice.     

An open study of risperidone liquid in the acute phase of schizophrenia

An open-label study was performed to investigate the clinical efficacy and mechanisms of risperidone liquid in ameliorating positive symptoms in the acute phase of schizophrenia. Eighty-eight patients (M/F: 50/38; age: 18-74 years;, mean +/- SD =32 +/- 16 years) meeting DSM-IV criteria for schizophrenia and treated with risperidone liquid (14 patients also used lorazepam) were evaluated with regard to their clinical improvement and extrapyramidal side effects using the positive and negative syndrome scale (PANSS) and the Simpson and Angus scale (SAS), while plasma concentrations of HVA and MHPG were analysed by HPLC-ECD before and 4 weeks after risperidone liquid administration. Patients showing a 50% or greater improvement in PANSS scores were defined as responders. An improvement in the PANSS scores related to excitement, hostility and poor impulse control was seen within 7 days after administration of risperidone liquid, and an improvement with regard to hallucinatory behaviour and uncooperativeness was seen within 14 days after its administration. Finally, 68% of patients were classified as responders 4 weeks after risperidone liquid administration. The scores of SAS were not changed after risperidone liquid administration. Pretreatment plasma homovanillic acid (HVA) levels in the responders (8.1 +/- 2.9 ng/ml) were higher than those in nonresponders (5.9 +/- 1.9 ng/ml). In addition, a negative correlation was seen between the changes in plasma HVA levels and the percentage of improvement in PANSS scores. On the other hand, there were no differences between pretreatment plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) levels and those of nonresponders. These results suggest that risperidone liquid is effective and well tolerated for the treatment of acute phase schizophrenic patients, and that efficacy is related to its affects on dopaminergic activity, not noradrenergic activity.