1. 3 Department of Psychology, Sheppard Pratt, Baltimore, USA
VALACYCLOVIR AUGMENTATION FOR COGNITIVE AND FUNCTIONAL REMEDIATION IN SCHIZOPHRENIA
Triptish Bhatia1, N.N. Mishra1, K.M. Prasad2, Faith Dickerson3, Vishwajit L. Nimgaonkar4, Smita N. Deshpande5
1 GRIP-Yoga Project, Department of Psychiatry, PGIMER-Dr. R.M.L. Hospital, New Delhi
2 Department of Psychiatry, University of Pittsburgh, School of Medicine and Graduate School of Public Health, Pittsburgh, USA
3 Department of Psychology, Sheppard Pratt, Baltimore, USA
4Departments of Psychiatry and Human Genetics, University of Pittsburgh, School of Medicine and Graduate School of Public Health, Pittsburgh, USA
5 Head, Department of Psychiatry, PGIMER-Dr. R.M.L. Hospital, New Delhi
Abstract:
Background: In a randomized double-blind placebo-controlled trial (Prasad et al 2012) supplemental Valacyclovir (VAV) was found to alleviate impairments in cognitive domains in early course Schizophrenia (SZ) patients exposed to HSV-1. The present replication and extension study, funded by the Stanley Medical Research Institute, is planned to study augmentation by VAV for cognitive and functional change with treatment as usual in an adequately powered representative sample of early course schizophrenia.
Design: In a randomized double blind placebo controlled design, early course SZ / schizoaffective disorder (SZA) patients (n=68) (ill for seven years or less) exposed to HSV1 will be randomized to placebo (PLA) or drug (valacyclovir 1.5 g by mouth, twice daily) for four months along with treatment as usual. All participants will be assessed on clinical symptoms, cognitive variables, overall function (including social function) and side effects at baseline, after four months of medication, and one month after stopping study drug.
Discussion: Power for cognitive differences was estimated using Prasad et al (2012) (VAV, n=9; Placebo, n=8). We anticipate 34 initial subjects, with 25 completers in each arm. This sample size has 80% power to detect d=0.8, consistent with the effect sizes noted in the Prasad study ( ). The activity of valacyclovir is specific to HSV 1, so the neurocognitive improvements may be related to reduction of viral load in host cells. This approach could provide a novel strategy to treat cognitive impairments in HSV1 exposed schizophrenia patients.
Prasad KM, Eack SM, Keshavan MS, Yolken RH, Iyengar S, Nimgaonkar VL (2012) Antiherpes Virus-Specific Treatment and Cognition in Schizophrenia: A Test-of-Concept Randomized Double-Blind Placebo-Controlled Trial, Schizophr Bull. 2012 Mar 23.
Introduction:
Patients with SZ have impairment in several cognitive domains1, for which treatment is not yet available
Stanley Medical Research Institute (SMRI) funded studies among others suggest that certain Herpes viruses are associated with cognitive impairment among SZ patients as well as healthy persons
Whether HSV-1/CMV exposure is also associated with similar social/functional impairment in SZ is unknown. Such changes are arguably more important to patients and relatives.
Table 2: Schedule of evaluations.
Time (weeks) → 2 4 8 12 16
20 weeks
Informed consent √
Evaluations ↓
Baseline assessment /PLA Run in (2 weeks)
VAV / PLA
Follow up
Diagnosis
Physical exam/labs
Clinical severity
Cognition
Social Function
Side effects
Preliminary Study (Prasad et al. (2012):
A double-blind placebo-controlled design
HSV1-seropositive SZ subjects (n=24) randomized to receive either valacyclovir (n = 12) or placebo (n =12)
Adjunct to treatment as usual VAV or PLA were given for 18 weeks
Psychopathology, side effects and cognition were tested at baseline and at the end of the trial
VAV group improved in verbal memory (1.14), working memory (d: 0.79), and visual object learning (0.97) compared with PLA group.
Current status :
Commencement: First February, 2013 after ethics approval
A manual of operations was formalized very methodically
Patients who showed interest in the study were referred to research personnel by the clinicians for review for inclusion criteria.
Those who meet inclusion criteria are explained about the study in detail and written informed consent is obtained.
Then blood sample is drawn for lab tests and HSV titers.
Those who have normal lab parameters and are positive on HSV are included in the study.
Present Study: Aims:
Can Valacyclovir (VAV) augmentation benefit cognitive function in an Indian HSV-1 exposed Early Course Schizophrenia (ECSZ) sample treated with antipsychotic drugs?
Do the beneficial effects of VAV augmentation include functional improvement?
Hypothesis:
VAV augmentation improves (a) cognitive and (b) overall function among HSV-1 exposed Early Course Schizophrenia patients.
Enrollment in the Study till March 31, 2013
Design: Sample Size:
Considered for inclusion=(n=22)
Excluded (n=10)
¨  Not meeting inclusion criteria (n=7)
¨  Declined to participate (n=3)
Analysis= Not yet started
Visit 0=1 Visit 1=1
Visit 2=3 Visit 4=3
Lost to follow-up =None
Discontinued intervention =None
Allocation
Analysis
Follow-Up
Randomized (n=8)
Enrollment
156 referrals: clinical Dx SZ/ SZA stable meds 1 month
Diagnostic Evaluation
68 HSV1 + pts. enter study (34 VAV, 34 PLA)
50 patients complete study
(25 VAV, 25 PLA)
114 confirmed SZ/SZA; test for HSV1
Exclude 42 Patients
Exclude 46 Patients
18 Patients dropout
Consented=12
HSV –ve=3
Lab reports not normal=1
Outcome Variables and Instruments
Clinical Severity
Positive and Negative Symptoms Scale (PANSS)
CGI
Cognition
Trail Making Test (TMT)
Computerized Neurocognitive Battery (CNB)
Overall function
Independent Living Skills Survey (ILSS)
Sheehan’s disability scale (SDS)
Global Assessment of Functioning (GAF)
Quality of Life Scale
Side Effects:
Abnormal Involuntary Movement Scale
Barnes Akathisia Scale
Database:
Database was prepared in Microsoft Access specifically for this trial. All cognitive, clinical, physical, and side effects data is entered in this database visit wise.
Table 1: Eligibility criteria (identical to our recently completed SMRI/PITT study).
Inclusion Criteria
Exclusion Criteria
Written informed consent.
Substance abuse in the past month/dependence past 6 months.
Both genders, ages years
History / current medical /neurological illnesses e.g., epilepsy.
Schizophrenia / schizoaffective disorder (DSM IV).
Pregnancy.
Duration of psychosis ≤7 years.
History of immune disorders, HIV infection, renal dysfunction or receiving immune-suppressants.
Stable dose of antipsychotics for > 1 month, continued throughout the study.
Receiving regular antiviral therapy.
Score 4 or more on one or more items of the Positive and Negative Syndrome Scale.
History of hypersensitivity to Valacyclovir.
Exposed to HSV-1: serum antibody assays.
Mental retardation as defined in DSM IV.
Data Analysis:
To compare VAV with PLA a t-test of difference scores will be used.
Regression analyses will be used to assess the potential effects of demographic or clinical covariates
For repeated measures, we will use analysis of covariance models with fixed treatment effects and trajectories as random effects.
Conclusion:
If replicated, this approach could provide a novel strategy to treat cognitive impairments in a subgroup of schizophrenia subjects who can be reliably identified using a blood test.
Acknowledgment: We are thankful to Robert H Yolken for his pioneer work in the field. Thanks to all research personnel
Source of support: Stanley Medical Research Institute
Contact us: Dr .Triptish Bhatia;
Prof. S.N.Deshpande;