Rahul Sarkar

Hepatitis C treatment in “difficult-to-treat” psychiatric patients with pegylated interferon-alpha and ribavirin: Response and psychiatric side effects†

We investigated and compared the results of treating the chronic hepatitis C (HCV) infection of different groups of psychiatric‐risk patients and controls with pegylated interferon alpha (pegIFN‐α) plus ribavirin. Seventy patients were prospectively screened for psychiatric disorders. Seventeen patients without psychiatric diseases or drug addiction (controls), 22 patients with psychiatric disorders, 18 patients who had received methadone substitution treatment and 13 patients who were former drug users were treated with pegIFN‐α plus ribavirin. Sustained virological response (SVR), adherence, and psychiatric side effects (using the Montgomery‐Asberg Depression Rating Scale and the Brief Psychiatric Rating Scale) in the groups were compared. An SVR was found in 58.6% of all patients: 58.8% of the controls, 50% of psychiatric patients, 72.2% of methadone patients, and 53.8% of former drug users. Methadone‐substituted patients and former drug users had significantly higher dropout rates. Scores for neither depressive nor psychotic symptoms differed significantly between groups during treatment. However, the controls had lower pretreatment scores, followed by a significant higher increase to maximum scores. A stepwise logistic regression model showed that only genotype, not group (control, psychiatric, methadone, or former drug abuse), type of psychiatric diagnosis (affective disorder, personality disorder, or schizophrenic disorder), depression scores before and during treatment, change in depression score, antidepressive treatment, sex, or liver enzymes before treatment, was associated with SVR. Conclusion: In an interdisciplinary treatment setting psychiatric diseases and/or drug addiction did not negatively influence psychiatric tolerability of and antiviral response rate to HCV treatment with pegIFN‐α and ribavirin. (HEPATOLOGY 2007.)

Escitalopram for the Prevention of Peginterferon-α2a–Associated Depression in Hepatitis C Virus–Infected Patients Without Previous Psychiatric Disease: A Randomized Trial

BACKGROUND Depression is a major complication during treatment of chronic hepatitis C virus (HCV) infection with interferon-α (IFN-α). It is unclear whether antidepressants can prevent IFN-induced depression in patients without psychiatric risk factors. OBJECTIVE To examine whether preemptive antidepressant treatment with escitalopram can decrease the incidence or severity of depression associated with pegylated IFN-α in HCV-infected patients without a history of psychiatric disorders. DESIGN Randomized, multicenter, double-blind, prospective, placebo-controlled, parallel-group trial. (ClinicalTrials.gov registration number: NCT00136318) SETTING 10 university and 11 academic hospitals in Germany. PATIENTS 181 HCV-infected patients with no history of psychiatric disorders enrolled between August 2004 and December 2008. INTERVENTION Escitalopram, 10 mg/d (n = 90), or placebo (n = 91) administered 2 weeks before and for 24 to 48 weeks during antiviral therapy. MEASUREMENTS The primary end point was the incidence of depression, defined as a Montgomery-Asberg Depression Rating Scale (MADRS) score of 13 or higher. Secondary end points were time to depression, incidence of major depression according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, quality of life, sustained virologic response, tolerability, and safety. RESULTS 32% (95% CI, 21% to 43%) of the patients in the escitalopram group developed a MADRS score of 13 or higher compared with 59% (CI, 48% to 69%) in the placebo group (absolute difference, 27 percentage points [CI, 12 to 42 percentage points]; P < 0.001). Major depression was diagnosed in 8% of the patients in the escitalopram group and 19% in the placebo group (absolute risk difference, 11 percentage points [CI, 5 to 15 percentage points]; P = 0.031). Tolerability and safety parameters did not differ between the groups. In the escitalopram group, 56% (CI, 46% to 66%) of patients achieved a sustained virologic response compared with 46% (CI, 37% to 57%) in the placebo group (P = 0.21). LIMITATIONS Results might not be generalizable to patients with previous psychiatric disease. Some patients withdrew or developed temporary elevated MADRS scores after randomization but before the study medication was started. CONCLUSION Prophylactic antidepressant treatment with escitalopram was effective in reducing the incidence and severity of IFN-associated depression in HCV-infected patients without previous psychiatric disease. PRIMARY FUNDING SOURCE Roche Pharma and Lundbeck.

Switching schizophrenia patients from typical neuroleptics to aripiprazole: Effects on working memory dependent functional activation

BACKGROUND Deficits in working memory (WM) are a core symptom of schizophrenia patients and have been linked to dysfunctional prefrontal activation, which might be caused by a mesocortical hypodopaminergic state. Aripiprazole--a partial dopamine antagonist--is a novel antipsychotic, which increases frontal dopamine concentrations in preclinical studies. However, little is known about specific medication effects on the modulation of frontal activation during WM performance. METHODS We measured BOLD-response during a WM task in a longitudinal fMRI-study in eleven schizophrenia patients first when they received conventional antipsychotics (T1) and a second time after they had been switched to aripiprazole (T2). A healthy control group matched for age, handedness and gender was investigated at two corresponding time points. Data was analyzed with SPM5 in a 2 x 2 x 2 design (groupxsessionxtask). RESULTS Schizophrenia patients showed fewer correct responses compared to healthy controls at T1 and a trend-wise normalization at T2. The task activated the fronto-parietal network during the contrast 2-back>0-back in all participants. At T1 patients revealed a hypoactivation in the dorsal anterior cingulate cortex (ACC), which normalized after switch to aripiprazole and correlated with improved task performance. This was due to a significant increase in the patients group while the control group did not change, as corroborated by a significant groupxtime interaction in this region. CONCLUSIONS This study showed for the first time that the partial dopamine antagonist aripiprazole increases BOLD-signal during a WM task in the cognitive part of the ACC in schizophrenia patients, which may reflect its beneficial effect on cognitive deficits.

Gender differences in psychotic bipolar mania

OBJECTIVE This study examined gender differences in the prevalence and types of psychotic symptoms in bipolar mania. METHODS Participants were drawn from consecutive admissions to the psychiatric clinic in Chemnitz, Germany, in 2005. The diagnosis of bipolar disorder, manic episode was made within 24 hours of admission, and the severity of mania was assessed using the Young Mania Rating Scale (YMRS) and the German version of the Altman Self-Rating Mania Scale. Data collected for each patient included age at the onset of bipolar illness, number of previous episodes, social functioning between episodes, and duration of hospitalization for the index episode. Based on the Task Force for Methods and Documentation in Psychiatry system, psychotic symptoms were classified as hallucinations (visual, auditory, olfactory, tactile, acousma, somatic); delusions (paranoid, reference, guilt, grandeur, religious, erotomania, hypochondriac, poverty, jealousy); and ego disorder (thought control, thought broadcasting). RESULTS One hundred thirty-seven women and 109 men met the criteria for an acute manic episode, of whom 93 women and 62 men had psychotic symptoms. Compared with psychotic men, psychotic women had more delusions and hallucinations, both overall and per patient, and more delusions of reference and paranoid delusions. Psychotic women had more mixed states compared with psychotic men. Psychotic women differed from both psychotic men and nonpsychotic women on a number of clinical and social variables: they had higher YMRS scores and more previous episodes of depression despite an earlier onset of illness. CONCLUSION Women with bipolar mania exhibited a specific pattern of psychotic symptoms that appeared to be associated with greater severity of the acute episode, more mixed states, and a more severe course of illness.

Aripiprazole augmentation in treatment-refractory obsessive–compulsive disorder

Obsessive–compulsive disorder (OCD) responds preferentially to cognitive behavioural therapy (CBT) and to pharmacological treatment such as antidepressant drugs like serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants with a predominantly serotonergic mechanism (Math and Janardhan Reddy 2007). Approximately half of OCD patients treated with an adequate trial of SSRIs fail to fully respond and continue to exhibit significant symptoms (Bloch et al 2006). Aripiprazole is a quinolinone derivative with a high affinity for dopamine D2 and D3 receptors as well as serotonin 5HT1A, 5-HT2A and 5-HT2B receptors. Aripiprazole is an atypical antipsychotic medication that works via partial dopaminergic, 5-HT1A, 5-HT2A and 5-HT2B receptor agonist activity (Rugino and Janvier 2005). We report a case of an OCD patient in whom a treatment regimen with escitalopram was successfully augmented with aripiprazole.

Management of Mental Health Problems Prior to and During Treatment of Hepatitis C Virus Infection in Patients With Drug Addiction

Psychiatric comorbidity is a common problem in patients with substance use disorders. Patients with psychiatric diseases and/or substance abuse have an increased risk for hepatitis C virus (HCV) infection. Furthermore, psychiatric problems occur frequently during antiviral treatment and may be associated with the use of interferon alpha (IFN-α) but also with the primary psychiatric condition. As a consequence, substance abuse and/or acute psychiatric problems are still important reasons for nontreatment of chronic HCV infection. However, prospective and controlled data from recent years showed that if an interdisciplinary treatment is provided, patients with substance use disorders and/or psychiatric diseases do not differ regarding sustained virologic response or IFN-α-associated complications such as depression when compared with controls. Moreover, depression as the most important acute IFN-α-associated psychiatric adverse event can be acutely treated or even prevented by antidepressant pretreatment. Other, more rare but severe complications such as mania, psychotic symptoms, or delirium need individual psychiatric interventions.

Three Cases of Successful Tryptophan Add-On or Monotherapy of Hepatitis C and IFNα-Associated Mood Disorders

BACKGROUND Interferon-alpha (IFN(alpha))-associated mood disorder is a major complication of treatment for chronic hepatitis C. METHOD The authors report on three patients infected with chronic hepatitis C showing severe depressive symptoms during or after IFN(alpha) treatment. Because patients had lowered tryptophan blood levels and did not response to antidepressants, they received tryptophan up to a dosage of 1,000 mg/day as mono- or add-on treatment. RESULTS Tryptophan, used as augmentation or monotherapeutic treatment, led to a significant improvement of depressive symptoms in all three patients. CONCLUSION A tryptophan deficit seems to be involved in the pathophysiology of persistent mood changes during and after IFN(alpha) treatment.

Levetiracetam as monotherapy or add-on to valproate in the treatment of acute mania-a randomized open-label study.

IntroductionAnticonvulsants are a mainstay in the treatment of bipolardisorder. Valproate (VPA) and carbamazepine have beenwidely accepted in the treatment of acute mania and mixedstates. There is evidence that while combination treatmentof VPA or lithium with other anticonvulsants or atypicalneuroleptics improves manic symptoms better than mono-therapy, it also increases the risk of side effects that oftenlead to treatment discontinuation (Smith et al. 2007; Lin etal. 2006). Thus, new adjunctive treatments with well-tolerated effective drugs are required. Levetiracetam(LEV) is a new antiepileptic drug providing wide clinicalefficacy in partial and in generalized epilepsy (Ben-Menachem and Gilland 2003). The mechanism of its actionis not completely known so far but might include anatypical GABAergic effect (Patsalos 2000). To furtherdefine the clinical profile of LEV, we conducted arandomized, open trial in manic patients treated either withVPA monotherapy or with adjunctive LEVover a period of10 weeks.Materials and methodsThirty patients met the Diagnostic and Statistical Manual ofMental Disorders IV criteria for mania. The Study inclusioncriterion for patients was a Young Mania Rating Scale(YMRS) score greater than 20, where the cutoff level was aYMRS score greater than or equal to 40. Patients were notincluded if they had one or more comorbid axis I or axis IIdiagnoses other than bipolar I disorder. All patients gaveoral and written informed consent approved by the localEthics Committee. Patients were randomized to either themonotherapy group with VPA or to the combinationtreatment group with VPA and LEV. Dose adjustment wasbased on clinical impression, rating scale scores, andplasma levels for VPA (50–120 mg/l) at each of the fourvisits. Maximum doses for LEV were set at 5,000 mg/dayand for VPA at 3,000 mg/day or when plasma levels of120 mg/l were achieved. Rescue medication includedlorazepam up to 2 mg/day and zopiclone 7.5 mg/qhs.Patients were seen and rated weekly (visits 1 and 2), atweek 5 (visit 3), and after further 5 weeks (visit 4) at theend of this study. At all visits, patients underwent thefollowing rating scale scores: YMRS, Hamilton DepressionScale (HAM-D), Clinical Global Impression Scale forBipolar Disorder (CGI-BP), and the Global Assessment ofFunctioning Scale (GAF). A positive response was oper-ationalized as a 50% drop in YMRS rating and consideredthe primary outcome measure. Rating scale assessmentsand serum levels of both medications and, if necessary,

Sadness and mild cognitive impairment as predictors for interferon-alpha-induced depression in patients with hepatitis C

BACKGROUND Antiviral therapy with interferon-alpha (IFN-α) for hepatitis C virus (HCV) infection is associated with increased risk for depression. AIMS To identify clinical predictors for IFN-α-induced depression during antiviral therapy for HCV infection. METHOD Depression (defined with the Montgomery-Åsberg Depression Rating Scale (MADRS)) was evaluated before and during antiviral treatment in 91 people with chronic HCV infection without a history of psychiatric disorders. Cognitive function was evaluated using the Trail Making Test A/B (TMT A/B). (Trial registration at ClinicalTrials.gov: NCT00136318.) RESULTS Depression during antiviral therapy was significantly associated with a baseline MADRS score of 3 or higher (P = 0.006). In total, 89% (n = 16) of patients who had a baseline score >0 for the single item sadness developed depression. Poor baseline performance in the TMT A (P = 0.027) and TMT B (P = 0.033) was predictive for severe depression. CONCLUSIONS Pre-treatment screening for subthreshold depressive and cognitive symptoms will help to identify those at risk for IFN-α-associated depression among patients with chronic hepatitis C.

Emotional vulnerability and cognitive control in patients with bipolar disorder and their healthy siblings: a pilot study.

Scheuch K, Bräunig P, Gauggel S, Kliesow K, Sarkar R, Krüger S. Emotional vulnerability and cognitive control in patients with bipolar disorder and their healthy siblings: a pilot study. Objective: There is evidence that, even in remission, patients with bipolar disorder (BD) have deficits in cognitive function and emotional regulation. Siblings of patients with BD are also reported to exhibit minor dysfunction in neuropsychological domains. In this study, we examined the interference of acute mood state with reaction time (RT) and response inhibition in euthymic patients with BD, in their healthy siblings and in healthy controls. Methods: A total of 34 patients with bipolar I disorder, 22 healthy siblings and 33 healthy controls performed a stop-signal paradigm after induction of a transient intense sadness and a relaxed mood state. The differences in RT and the response inhibition were compared between the groups. Results: Euthymic patients with BD displayed a higher emotional reactivity compared with their siblings and with controls. Compared with controls, patients with BD showed longer RTs in a relaxed mood state and a delay in response inhibition during emotional activation. Conclusions: The present study provides evidence for the clinical observation that patients with BD have shorter RTs when in a state of emotional arousal rather than in a relaxed state. Inhibitory deficits in these patients may be because of a too strong emotional arousal. The results show that in patients with BD, relaxation and emotional arousal are inversely associated with performance in a neuropsychological task. This is in contrast to findings in healthy individuals suggesting a dysbalance in emotional regulation in these patients.