Treatment predictors of extrapyramidal side effects in patients with tardive dyskinesia: results from Veterans Affairs Cooperative Study 394

Predictors for the development of tardive dyskinesia (TD) have been studied extensively over the years, yet there are few studies of predictors of the course of TD after it has developed. Moreover, few studies have examined predictors of the course of other extrapyramidal side effects (EPS) in patients maintained on neuroleptics. The purpose of this study was to determine which modifiable variables are important in the prediction of EPS in patients with persistent TD over a period of as long as 2 years. One hundred fifty-eight patients enrolled in the Veterans Affairs Cooperative Study 394 were included in this study. A linear mixed-effects (LME) analysis to estimate the Abnormal Involuntary Movement Scale score (for TD severity), Simpson-Angus Scale (for parkinsonism severity), and Barnes Akathisia Scale at any given time after intake assessment was performed. The severity of each of the TD and EPS outcomes at any given visit was predicted by their respective baseline severity scores. Additional predictors of a favorable course of TD included lower doses of antipsychotic medications and use of anticholinergic medications. Other predictors of a favorable course of EPS included younger age and the use of atypical antipsychotic medication (for rigidity) and the use of anticholinergic medication (for tremor). These findings indicate that clinician-modifiable factors related to medication usage can influence the outcome of TD and EPS in patients with persistent TD.     

Longitudinal patterns of antidepressant prescribing in primary care in the UK: comparison with treatment guidelines.

The objective of this study was to determine whether patients beginning therapy on the most common tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) differed in their likelihood of having antidepressant treatment that was consistent with recommended treatment guidelines in the UK. An analytical file constructed from a large general practitioner medical records database (DIN-LINK) from the UK for the years 1992-97 was constructed. A total of 16,204 patients with a new episode of antidepressant therapy who initiated therapy on one of the most often prescribed TCAs (amitriptyline, dothiepin, imipramine and lofepramine) or SSRIs (fluoxetine, paroxetine and sertraline) were analysed. A dichotomous measure was defined to indicate whether subjects were prescribed at least 120 days of antidepressant therapy at an adequate average daily dose within the first 6 months after initiation of therapy. Only 6.0% of patients initiating therapy on aTCA and 32.9% of patients initiating therapy on a SSRI were prescribed antidepressant treatment that was consistent with treatment guidelines. After controlling for observable characteristics, patients who initiated therapy on a SSRI were much more likely (odds ratio=7.473, p<0.001) to have a prescribed average daily dose and duration consistent with recommended treatment guidelines within the first 6 months of initiating therapy than were patients who initiated therapy on a TCA. These findings suggest that initial antidepressant selection is an important determinant of whether the subsequent course of treatment is consistent with current national guidelines for the treatment of depression in the UK.     

Ethnicity and the course of tardive dyskinesia in outpatients presenting to the motor disorders clinic at the Maryland psychiatric research center

BACKGROUND: Although newly emergent tardive dyskinesia (TD) is less of a concern, about one-fourth to one-third of patients on or previously on chronic first-generation antipsychotic agents have TD. The long-term course and outcome, as well as their predictors, are unknown. Earlier studies identify ethnicity as one of the risk factors for the development of TD, and case reports have noted a preponderance of African-American males in cohorts of patients with tardive dystonia. The current study examines the anatomic distribution and course of TD in a cohort of schizophrenia patients of European and African descent with TD who were referred to the Motor Disorders Clinic (MDC). METHODS: We evaluated data collected on 1149 TD patients who were given a focused neurologic examination for movement disorders. Movements were evaluated with the MPRC Scale for Involuntary Movements (IMS). All patients met RDC-TD criteria for diagnosis of persistent TD. One to 10-year follow-up data on 528 patients were evaluated to examine the course of TD following recommendations made to referring primary clinicians. Suggested interventions to referring primary clinicians included dose reduction of first-generation antipsychotic medication, or switching to a second-generation antipsychotic. RESULTS: Initial evaluation included 701 European American (EA) patients and 448 African-American (AA) patients. AA patients had a significantly higher proportion of males [chi(1) = 7.50, P < 0.05]. EA subjects had a higher mean age than AA patients 42.8 +/- 11.2 and 39.8 +/- 10.4, respectively [F(1,1147) = 22.27, P < 0.05]. Mean neuroleptic exposure (chlorpromazine equivalents) was similar in both groups after controlling for differences in age.Follow-up data analyzed in 528 patients (329 EA and 199AA) showed a significant ethnicity by TD interaction [F(1,504) = 4.26, P < 0.05]. Examination of body distribution of dyskinetic movements showed an effect of ethnicity. Subsequent analyses suggest EA patients experienced more improvement in TD over the course of follow up [F(1,319) = 22.39, P < 0.05] compared with AAs [F(1,189) = 1.58, P > 0.05]. These findings were unchanged when age, change in antipsychotic drug dose, and duration of follow-up were covaried. CONCLUSION: Reports from earlier studies note ethnicity (African descent) as a risk factor in the development of TD. Our study findings suggest ethnicity might be an important factor in predicting a poor course of TD.     

Alprazolam reversal of reserpine-induced depression in patients with compensated tardive dyskinesia

Two patients are described who developed neuroleptic drug-induced tardive dyskinesia (TD) secondary to the treatment of schizophrenia. In both patients, neuroleptic drug discontinuation brought about a decrease in the severity of the TD and an increase in schizophrenic symptomatology. Reserpine was added for both antipsychotic coverage and reported beneficial effects in the treatment of TD. The patients' schizophrenia was controlled using reserpine 1 mg/d; the TD dissipated in one patient and decreased in the other. After about seven weeks of reserpine therapy, both patients developed depressive symptoms that required the addition or alprazolam. Within a month of the initiation of alprazolam, the depressions had cleared. Alprazolam may block reserpine-induced increases in beta-adrenergic receptors in the brain and may account for the antidepressive effects in these two patients.     

Tardive dyskinesia and antipsychotics: a 5-year longitudinal study of frequency, correlates and course

The present study comprised a naturalistic, multicentre, 5-year study of course and correlates of tardive dyskinesia (TD). One hundred and sixty-six patients treated with risperidone were included during 1995/96 and followed once a year for 5 years. Mean age at inclusion was 38 years, and mean illness duration was 12 years. Tardive dyskinesia was assessed by the Abnormal Involuntary Movement Scale, and each patient's cognitive function was tested with a comprehensive computerised test battery. At study entry, 14% had TD according to a criterion index. Fifty percent were aware of it, but few reported distress. Age and sex did not correlate with TD, but schizophrenia and bipolar diagnoses did. The presence and intensity of TD correlated with all Positive and Negative Syndrome Scale for Schizophrenia symptom dimensions except the affective factor, but not with type of medication or chlorpromazine-equivalent levels. Tardive dyskinesia patients were cognitively impaired in tests reflecting mental speed, but not in other cognitive modalities. Over the 453 patient years of exposure, five patients developed TD and 14 became free of it. Our findings support the view that TD: (i) is a dynamic phenomenon; (ii) is only partly drug-induced; (iii) has a mild course during treatment with modern neuroleptics; and (iv) appears to have some correlation with mental slowness.     

Antidepressant use and resource utilization in the general practitioner setting in The Netherlands

OBJECTIVE: To assess antidepressant use and resource utilization in the general practitioner (GP) setting in the Netherlands following initiation of antidepressant therapy. DESIGN: Longitudinal study in a retrospective database. PARTICIPANTS: Sample of 869 patients from a new database in the Netherlands who initiated therapy on a selective serotonin re-uptake inhibitor (SSRI) or a tricyclic antidepressant (TCA). MAIN OUTCOME MEASURES: Mean length of antidepressant therapy within the first 90 days and resource utilization in the GP setting in the first 180 days following therapy initiation. RESULTS: (1) patients who initiated therapy on an SSRI were younger (48.6 years old versus 54.1 years old, p<0.01) and more likely to have a depression diagnosis (58% versus 30%, p<0.01) than patients who initiated therapy on a TCA; (2) patients who initiated therapy on an SSRI were more likely than patients who initiated therapy on a TCA (65% versus 52%, p<0.01) to have more than 30 days of therapy within the first 90 days and to receive antidepressant doses consistent with Dutch guidelines; (3) patients with greater than 30 days of antidepressant therapy within the first 90 days had more general practitioner visits than patients with 30 days of therapy or less (TCA patients: 9.6 versus 7.0; SSRI patients: 8.8 versus 6.9, p<0.01). CONCLUSIONS: Patients in the GP setting in the Netherlands who initiate therapy on SSRIs are more likely than patients who initiate therapy on TCAs to receive recommended doses and duration of therapy consistent with Dutch antidepressant treatment guidelines.     

Plasma concentrations, information and therapy adherence during long-term treatment with antidepressants.

The influence of information on drug plasma monitoring during long-term antidepressant therapy in fourteen ambulant, depressed patients was evaluated as variation in the L/D ratio time course. A larger variability in L/D ratio, with higher coefficient of variation and a poorer clinical outcome, was found in non-informed patients. The data support the hypothesis that verbal information on long-term drug monitoring of antidepressants could improve patients' adherence to therapy.     

千金藤立定治疗迟发性运动障碍30例

在原有抗精神病药治疗情况下,合用-千金藤立定(SPD)治疗迟发性运动障碍(TD)30例。SPD剂量50mg tid,一个疗程8wk。结果显效率23％,总有效率56％;大多数4wk内生效,亦有8wk才生效。SPD无明显副作用,未增多或加重抗精神病药副作用,精神病症状也未恶化。初步认为SPD治疗TD安全有效。     

Antidepressant selection and use and healthcare expenditures. An empirical approach

The purpose of this study was to evaluate whether 1-year total healthcare expenditures differed between patients who initiated therapy on a tricyclic antidepressant (TCA) or a selective serotonin reuptake inhibitor (SSRI) after controlling for initial antidepressant selection and antidepressant use pattern. A retrospective claims database covering a privately insured population in the US was used. Patients who initiated therapy in the outpatient setting (primary care or psychiatrist) were considered. Two-stage sample selection models were estimated that included controls for initial antidepressant selection and use pattern. The analyses indicated that: (i) self-selection due to initial antidepressant selection was a statistically significant determinant of expenditures for patients who initiated therapy on a TCA but not an SSRI; (ii) after controlling for initial antidepressant selection, antidepressant use pattern was a statistically significant and positive determinant of expenditures for both TCA and SSRI patients; and (iii) after controlling for initial antidepressant selection and use pattern, 1-year total direct healthcare expenditures were significantly lower for patients who initiated therapy on an SSRI than for patients who initiated therapy on a TCA.     

The Duke Somatic Treatment Algorithm for Geriatric Depression (STAGED) approach

Although there have been previously published algorithms for the treatment of depression, few have been rigorously studied in terms of outcome. We present the Duke Somatic Treatment Algorithm for Geriatric Depression (STAGED) approach, developed by clinicians in the Duke Mood Disorders Program. The algorithm consists of five stages based on treatment history. In developing the approach, we enrolled 228 depressed elderly patients in a National Institute of Mental Health-funded longitudinal study of depression. Patients were treated by geriatric psychiatrists using the algorithm as a guideline for treatment. Initially, 174 patients were treated with antidepressant medications, and 54 patients were treated with electroconvulsive therapy. Over the course of 18 months of treatment, 88.6% of patients responded, and 65.35% of patients were able to achieve full remission of symptoms. The STAGED approach appears to be a clinically useful method of successfully treating elderly depressed patients.     

Retrospective analysis of serum valproate levels and need for an antidepressant drug.

We sought to determine whether patients receiving valproate plus an antidepressant had significantly lower serum valproate levels before initiation of the antidepressant than those patients receiving valproate without an antidepressant. We further sought to identify the prevalence of antidepressant-induced mania and to determine if valproate provided a protective effect against antidepressant-induced mania. A computer database search from January 1, 1990-June 30, 1998, identified patients with bipolar or schizoaffective disorder treated with valproate. Patients receiving an antidepressant during valproate therapy were identified as the treatment group (9 patients), and the remaining patients served as the control group (17 patients). Serum valproate levels were recorded just before starting the antidepressant for the treatment group and monthly during a comparable period for the control group. The mean time to antidepressant initiation was 15 +/- 8 weeks. The mean serum valproate level just before antidepressant initiation was significantly lower for the treatment group compared with the mean serum valproate level averaged over 16 +/- 6 weeks for the control group (54 +/- 24 vs 73 +/- 13 microg/ml, p<0.05). Four patients (44%) developed antidepressant-induced mania. Three required discontinuation of the antidepressant; their serum valproate levels were 54, 60, and 71 microg/ml. Patients requiring the addition of an antidepressant had significantly lower valproate serum levels than those who did not require an antidepressant. Further study is necessary to determine whether higher serum valproate levels are needed for prevention of depressive symptoms in bipolar and schizoaffective disorders.     

Psychopharmacological treatment of depression, anxiety, irritability and insomnia in patients receiving interferon-alpha: a prospective case series and a discussion of biological mechanisms

We studied 60 patients receiving a 1-year course of interferon (IFN)-alpha therapy for chronic viral hepatitis. Patients underwent psychiatric assessment before starting the IFN-alpha therapy, and monthly throughout the therapy, using the Structured Clinical Interview for the DSM-III-R, the 17-item Hamilton Depression Rating Scale, the Beck Depression Inventory and the Spielberg State and Trait Anxiety Inventory. Five patients had a baseline diagnosis of major depression and 18 (30%) developed an IFN-alpha-induced psychiatric adverse effect; 12 of these 23 patients received psychopharmacological treatment (patients and clinicians jointly decided the need for treatment). Two of the five patients with baseline depression started an antidepressant treatment (paroxetine) together with the IFN-alpha and successfully completed the IFN-alpha therapy. Ten patients received treatment for the IFN-alpha-induced psychiatric adverse effects (depression in five patients, anxiety in two patients, severe irritability in two patients and insomnia in one patient). Depression was treated with paroxetine, amisulpride or levosulpiride; anxiety and insomnia were treated with benzodiazepines; and irritability was treated with thioridazine. Individual response to medications was measured with the Clinical Global Impression scale. Of the patients with IFN-alpha-induced depression, two received paroxetine (one showed a good response), two received amisulpride (one showed a good response) and one did not respond to levosulpiride but responded to paroxetine. The patients experiencing anxiety or insomnia responded well to benzodiazepines. One patient showed a good response, and one a poor response, to thioridazine for irritability. Only one patient interrupted the therapy because of psychiatric adverse effects. Overall, the 12 patients that received psychopharmacological treatment developed less severe psychopathological symptoms during the IFN-alpha therapy compared to the 11 patients who had untreated baseline depression or untreated IFN-alpha-induced psychiatric adverse effects. Thus, psychopharmacological management can successfully treat psychiatric symptoms in patients who are receiving IFN-alpha.     

Influence of aripiprazole on the antidepressant, anxiolytic and cognitive functions of rats

Recent research has suggested that cognitive disorders are a persistent trait of mental illnesses such as schizophrenia. Cognitive deficits in the course of schizophrenia may be due to the disease and/or drug therapy, especially with old-generation drugs. Several clinical experiments have indicated the beneficial effects of new-generation antipsychotics on cognitive processes in patients treated for mental disorders. Aripiprazole is a new, atypical antipsychotic with a unique mechanism of action, which may have positive effects on cognitive functions. The aim of this study was to investigate the effects of aripiprazole on spatial memory in the Morris water maze and antidepressant activity in the Porsolt test. In addition, we examined whether aripiprazole had any side effects in the chimney test. The behavioral tests showed that aripiprazole improved spatial memory in rats and had antidepressant and anxiolytic effects after a single treatment; however, aripiprazole impaired motor coordination after repeated administration. We concluded that aripiprazole could be an effective antipsychotic for the treatment of patients with schizophrenia or bipolar disorder who have associated anxiety and cognitive deficits.     

Syndrome of inappropriate antidiuretic hormone with imipramine

Among the various medications that have been associated with the development of syndrome of inappropriate antidiuretic hormone secretion (SIADH) are the tricyclic antidepressants. A 69-year-old man admitted for treatment of a depressive disorder that had not responded to trazodone was prescribed imipramine. Twenty-two days after initiation of therapy, the patient developed hyponatremia. The patient also had depressed serum osmolality and elevated urine sodium concentrations consistent with SIADH. With the discontinuation of imipramine, fluid restriction, and several doses of furosemide, normal serum sodium concentrations were attained. As antidepressant therapy was indicated, doxepin was selected. The patient maintained normal electrolyte values and water balance over the next two months of follow-up. No reports of doxepin-related SIADH were found in the literature; therefore, this agent may be considered as an alternative therapy in patients developing SIADH during antidepressant drug therapy.     

抗抑郁药的药效学性别异质性研究进展

抑郁症存在高患病率、高致残率和高自杀率的特点,严重影响患者的生活质量。药物治疗为该病的首选治疗方式,在临床治疗过程中,抗抑郁药物的药效学存在着明显的性别差异,可能与男女之间的大脑结构、性格、激素水平存在差异有关,但具体原因和机制尚未有统一结论。本文对抗抑郁药物的药效学性别异质性及其产生原因进行综述。     

Getting better, getting well: understanding and managing partial and non-response to pharmacological treatment of non-psychotic major depression in old age

In general, the pharmacological treatment of non-psychotic major depressive disorder in old age is only partially successful, with only approximately 50% of older depressed adults improving with initial antidepressant monotherapy. Many factors may predict a more difficult-to-treat depression, including coexisting anxiety, low self-esteem, poor sleep and a high coexisting medical burden. Being aware of these and other predictors of a difficult-to-treat depression gives the clinician more reasonable expectations about a patient's likely treatment course. If an initial antidepressant trial fails, the clinician has two pharmacological options: switch or augment/combine antidepressant therapies. About 50% of patients who do not improve after initial antidepressant therapy will respond to either strategy. Switching has several advantages including fewer adverse effects, improved treatment adherence and reduced expense. However, as a general guideline, if patients are partial responders at 6 weeks, they will likely be full responders by 12 weeks. Thus, changing medication is not indicated in this context. However, if patients are partial responders at 12 weeks, switching to a new agent is advised. If the clinician treats vigorously and if the patient and clinician persevere, up to 90% of older depressed patients will respond to pharmacological treatment. Furthermore, electroconvulsive therapy is a safe and effective non-pharmacological strategy for non-psychotic major depression that fails to respond to pharmacotherapy. Getting well and staying well is the goal; thus, clinicians should treat to remission, not merely to response. Subsequently, maintenance treatment with the same regimen that has been successful in relieving the depression strongly improves the patient's chances of remaining depression free.     

Antidepressants medications and the relative risk of suicide attempt

This study was conducted on patients (n=1283) of different ages, 924 males and 359 female. These patients were attended to poison unit at emergency hospital, Mansoura University during the period from January 2002 to December 2009. The aim of this study was to characterize patients on antidepressants after self-poisoning with suicidal intent regarding age, sex, type of current antidepressant therapy, and type of substances ingested in order to commit suicide. During the study period, 175 Para suicide patients were found with current antidepressants therapy and presented with self-poisoning using their antidepressant therapy or other medications. A substantial difference between different types of antidepressants was found. Para suicide risks for selective serotonin reuptake inhibitor were significantly low than those of tricyclic antidepressants, so in suicide prevention, risks and benefits of an antidepressant should be taken into account when choosing treatment for depressive patients. At the same time, depressed patients should be under close psychiatric assessment in order to prevent such possible suicidal attempts.     

Predicting treatment response to antidepressant medication using early changes in emotional processing

Antidepressants must be taken for weeks before response can be assessed with many patients not responding to the first medication prescribed. This often results in long delays before effective treatment is started. Antidepressants induce changes in the processing of emotional stimuli early in the course of treatment. In the current study we assessed whether changes in emotional processing and subjective symptoms over the first week of antidepressant treatment predicted clinical response after 4–8 weeks of treatment. Such a predictive test may shorten the time taken to initiate effective treatment in depressed patients. Seventy-four depressed primary care patients completed measures of emotional bias and subjective symptoms before starting antidepressant treatment and then again 1 week later. Response to treatment was assessed after 4–6 weeks. The performance of classifiers based on these measures was assessed using a leave-one-out validation procedure with the best classifier then tested in an independent sample from a second study of 239 patients. The combination of a facial emotion recognition task and subjective symptoms predicted response with 77% accuracy in the training sample and 60% accuracy in the independent study, significantly better than possible using baseline response rates. The face based measure of emotional bias provided good quality data with high acceptability ratings. Changes in emotional processing can provide a sensitive early measure of antidepressant efficacy for individual patients. Early treatment induced changes in emotional processing may be used to guide antidepressant therapy and reduce the time taken for depressed patients to return to good mental health.