Research Findings - International Research
INVEST Fellow: Anton Bespalov, Russia, 1994-1995
Marek GJ, Behl B, Bespalov AY, et al.
Glutamatergic (N-Methyl-D-Aspartate Receptor) Hypofrontality In Schizophrenia: Too Little Juice Or A Miswired Brain Molecular Pharmacology. 2009 Nov 23. [Epub ahead of print]
Dopamine D2 receptor blockade has been an obligate mechanism of action present in all medications which effectively treat positive symptoms of schizophrenia (e.g,, delusions and hallucinations) and have been approved by regulatory agencies since the 1950's. Blockade of 5-hydroxytrypatmine(2A) (5-HT(2A)) receptors plays a contributory role in the actions of the second generation of antipsychotic drugs, the so-called atypical antipsychotics. Nevertheless, substantial unmet medical needs remain for the treatment of negative symptoms and cognitive dysfunction. Recognition that dissociative anesthetics block the N-methyl-D-aspartate (NMDA) receptor channel has inspired a search for glutamatergic therapeutic mechanisms since ketamine and phencyclidine are known to induce psychotic-like symptoms in healthy volunteers and exacerabate the symptoms of schizophrenic patients. Current pathophysiological theories of schizophrenia emphasize that hypofunction of NMDA receptors in critical sites in local circuits modulate the function of a given brain region or control projections from one region to another (e.g., hippocampal-cortical or thalamocortical projections). The demonstration that a metabotropic glutamate2/3 (mGlu2/3) receptor agonist prodrug decreased both positive and negative symptoms of schizophrenia raised hopes that glutamatergic mechanisms may provide therapeutic advantages. In addition to discussing activation of mGlu2 receptors with mGlu2/3 receptor agonists or mGlu2 receptor positive allosteric modulators (PAMs), the authors also discuss other methods that may potentially modulate circuits with hypofunctional NMDA receptors such as glycine transporter (GlyT1) inhibitors and mGlu5 receptor PAMs. The hope is that by modulating glutamatergic neurotransmission, the dysfunctional circuitry of the schizophrenic brain (both local circuits and long-loop pathways) will be improved.
INVEST-CTN Fellow: Amit Chakrabarti, India, 2007-2008; HHH, 2002-2003
Mailankot M, Jayalekshmi H, Chakrabarti A, et al.
Effect of Alpha-Tocopherol Supplementation On Renal Oxidative Stress And Na+/K+ -Adenosine Triphosphatase In Ethanol Treated Wistar Rats Indian Journal of Experimental Biology. 2009 Jul;47(7):608-610.
Ethanol intoxication resulted in high extent of lipid peroxidation, and reduction in antioxidant defenses (decreased GSH, GSH/GSSG ratio, and catalase, SOD and GPx activities) and (Na+/K+)-ATPase activity in kidney. Alpha-tocopherol treatment effectively protected kidney from ethanol induced oxidative challenge and improved renal (Na+/K+)-ATPase activity. Ethanol induced oxidative stress in the kidney and decreased (Na+/K+)-ATPase activity could be reversed by treatment with ascorbic acid.
PMID: 19761047 [PubMed - in process]
HHH Fellow: Artur de Andrade, Brazil, 1991-1992
Alexandrino-Silva C, Pereira ML, Bustamante C, et al.
Suicidal Ideation Among Students Enrolled In Healthcare Training Programs: A Cross-Sectional Study. Revista Brasileira de Psiquiatria. 2009 Oct 16. pii: [Epub ahead of print]
This study aimed to assess the presence of suicidal ideation, depressive symptoms and symptoms of hopelessness in three healthcare training programs. The study's population comprised all students enrolled at the Medical School of the FundaŤ‹o do ABC, Brazil, from 2006 to 2007 compared to students enrolled in nursing and pharmacy programs. We applied the Beck Scale for Suicidal Ideation, the Beck Depression Inventory and the Beck Hopeless Scale to assess psychiatric symptomatology. The general response rates of the medical, nursing, and pharmacy students were 56%, 56% and 61%, respectively. There was no difference regarding the presence of suicidal ideation among medical, nursing and pharmacy students. There was also no difference regarding the presence of either depression or hopelessness in medical students in comparison to nursing and pharmacy students. In comparison to nursing and pharmacy students, significantly higher severity rates in terms of hopelessness were observed only among medical students. Although the authors did not observe significant differences regarding suicidal ideation and depression among the three healthcare programs, these findings suggest that the presence of suicidal ideation is indeed a source of concern. Early identification of these symptoms is crucial in order to offer appropriate support and treatment and prevent deaths by suicide.
PMID: 19838592 [PubMed - as supplied by publisher]
HHH Fellow: Sergey Dvoryak, Ukraine, 1999-2000
Booth RE, Lehman WE, Dvoryak S, et al.
Interventions With Injection Drug Users In Ukraine. Addiction. 2009 Aug 4. [Epub ahead of print]
The aim of the study was to assess the effectiveness of a brief human immunodeficiency virus (HIV) testing and counseling intervention compared to a more time-consuming and expensive street-based intervention with injection drug users (IDUs). Design Cross-over experimental design in which 900 IDUs were recruited, followed by a 'wash-out' period with no recruitment, a reversal of intervention assignment areas and an additional recruitment of 900 IDUs with baseline and 6-month follow-up assessments. Setting Kiev, Odessa and Makeevka/Donesk Ukraine. Participants A total of 1798 IDUs. Measurements HIV testing and audio computer-assisted self-interview (ACASI) data on socio-demographics, drug use and injection and sex-related risk behaviors. Participants in both conditions reduced their injection and sex risks significantly; however, there was little difference in outcomes between conditions. IDUs who knew they were HIV-infected at baseline were significantly more likely to practice safe sex than those unaware or HIV-negative; those who first learned that they were infected at baseline changed their safe sex practices significantly more than those who already knew that they were infected at baseline and those who were HIV-negative. Younger IDUs and those injecting for a shorter period of time reported higher injection and sex risk behaviors following interventions. Conclusions Awareness of HIV infection by street-recruited drug injectors is associated with reduced sex risks. Additional interventions are required for younger IDUs and those injecting for shorter periods of time.
HHH Fellow: Alisher Latypov, Tajikistan, 2002-2003
Beyrer C, Patel Z, Stachowiak JA, et al.
Characterization of the Emerging HIV Type 1 and HCV Epidemics among Injecting Drug Users in Dushanbe, Tajikistan. AIDS Research and Human Retroviruses. 2009 Aug 18. [Epub ahead of print]
Abstract: This study aimed to determine HIV, HCV, and syphilis prevalence and correlates, and to characterize the molecular epidemiology of HIV-1 among injecting drug users (IDUs) in Dushanbe, Tajikistan. A cross-sectional study assessing risk factors for HIV and HCV through an interview administered survey was conducted. A total of 491 active adult IDUs were recruited from May to November 2004 in Dushanbe, Tajikistan. HIV-1 antibody status was determined with rapid testing and confirmed with ELISA. HCV antibody testing was conducted using a BIOELISA HCV kit. HIV-1 subtyping was done on a subset with full-length sequencing. Correlates of HIV and HCV infection were assessed using logistic regression. Overall prevalence of HIV was 12.1%, HCV was 61.3%, and syphilis was 15.7%. In a multivariate logistic regression model controlling for gender and ethnicity, daily injection of narcotics [odds ratio (OR) OR 3.22] and Tajik nationality (OR 7.06) were significantly associated with HIV status. Tajik nationality (OR 1.91), history of arrest (OR 2.37), living/working outside Tajikistan in the past 10 years (OR 2.43), and daily injection of narcotics (OR 3.26) were significantly associated with HCV infection whereas being female (OR 0.53) and always using a sterile needle (OR 0.47) were inversely associated with HCV infection. Among 20 HIV-1-positive IDU with specimens available for typing, 10 were subtype A, 9 were CRF02_AG, and one was an A-CRF02_AG recombinant. Epidemics of HIV-1, HCV, and drug use are underway in Dushanbe. The molecular epidemiology is distinctive, with West African variants accounting for roughly 50% of prevalent infections. Targeted prevention programs offering both needle exchange programs and opiate substitution therapies are urgently called for to prevent the further spread of HIV and HCV in Tajikistan.
HHH Fellow: Isidore Obot, Nigeria, 1991-1992
Benegal V, Chand PK, Obot IS.
Packages of Care For Alcohol Use Disorders In Low- and Middle-Income Countries
PLoS Medicine. 2009 Oct;6(10):e1000170. Epub 2009 Oct 27.
In the fourth in a series of six articles on packages of care for mental disorders in low- and middle-income countries, Vivek Benegal and colleagues discuss the treatment of alcohol use disorders. PMID: 19859536 [PubMed - in process]
HHH Fellow: Flavio Pechansky, Brazil, 1993-1994
von Diemen L, De Boni R, Kessler F, et al.
Risk Behaviors For HCV- and HIV-Seroprevalence Among Female Crack Users In Porto Alegre, Brazil. Archives of Women's Mental Health. 2009 Sep 16. [Epub ahead of print]
Several studies have shown a high prevalence of HIV-seropositive status among crack users, though most refer to North American populations. Few studies evaluate HCV prevalence among female crack users. In addition, there is a particular lack of data about risk behaviors and HIV/HCV prevalence in this population around the world. In order to ascertain the HIV/HCV serostatus and associated risk behaviors for infection of female crack users of Porto Alegre, Brazil. A cross-sectional study of a convenience sample of 73 current female crack users was conducted. Subjects answered NIDA's Risk Behavior Assessment and an AIDS Information Questionnaire. In addition, blood was collected from subjects for HIV/HCV tests. The overall prevalence of HIV was 37.0%; HCV seroprevalence was 27.7%; of 15.1% the sample was co-infected with HIV and HCV. Four years of schooling or fewer (OR 4.72-CI 95%; 1.49-14.99) and having three or more HIV tests in one's lifetime (OR 4.26-CI 95% (1.29-14.04)) were associated with HIV infection (after multivariate logistic regression). The single greatest risk factor for HCV infection was having 4 years of schooling or fewer (OR 4.51-CI 95%; 1.18-17.27). We found a very high prevalence of HIV and HCV infection among female crack users, and low education was the most significant risk factor associated with both infections.
PMID: 19760050 [PubMed - as supplied by publisher]
HHH Fellow: Vladimir Stempliuk, Brazil, 2003-2004
Oliveira LG, Barroso LP, Wagner GA, et al.
Drug Consumption Among Medical Students In S‹o Paulo, Brazil: Influences Of Gender and Academic Year. Revista Brasileira de Psiquiatria. 2009 Sep;31(3):227-239.
The objective of the study was to analyze alcohol, tobacco and other drug use among medical students. Over a five-year period (1996-2001), the authors evaluated 457 students at the Universidade de S‹o Paulo School of Medicine, located in S‹o Paulo, Brazil. The students participated by filling out an anonymous questionnaire on drug use (lifetime, previous 12 months and previous 30 days). The influence that gender and academic year have on drug use was also analyzed. During the study period, there was an increase in the use of illicit drugs, especially inhalants and amphetamines, among the medical students evaluated. Drug use (except that of marijuana and inhalants) was comparable between the genders, and academic year was an important influencing factor. Increased inhalant use was observed among the medical students, especially among males and students in the early undergraduate years. This is suggestive of a specific behavioral pattern among medical students. These findings corroborate those of previous studies. The authors conclude that inhalant use is on the rise among medical students at the Universidade de S‹o Paulo School of Medicine. Because of the negative health effects of illicit drug use, further studies are needed in order to deepen the understanding of this phenomenon and to facilitate the development of preventive measures.
PMID: 19784490 [PubMed - in process]
HHH Fellow: Olga Toussova, Russia, 2001-2002
Kruse GR, Barbour R, Heimer R, et al.
Drug Choice, Spatial Distribution, HIV Risk, And HIV Prevalence Among Injection Drug Users In St. Petersburg, Russia Harm Reduction Journal. 2009 Jul 31;6:22.
The HIV epidemic in Russia has been driven by the unsafe injection of drugs, predominantly heroin and the ephedrine derived psychostimulants. Understanding differences in HIV risk behaviors among injectors associated with different substances has important implications for prevention programs. The authors examined behaviors associated with HIV risk among 900 IDUs who inject heroin, psychostimulants, or multiple substances in 2002. Study participants completed screening questionnaires that provided data on sociodemographics, drug use, place of residence and injection- and sex-related HIV risk behaviors. HIV testing was performed and prevalence was modeled using general estimating equation (GEE) analysis. Individuals were clustered by neighborhood and disaggregated into three drug use categories: Heroin Only Users, Stimulant Only Users, and Mixed Drug Users. Among Heroin Only Users, younger age, front/backloading of syringes, sharing cotton and cookers were all significant predictors of HIV infection. In contrast, sharing needles and rinse water were significant among the Stimulant Only Users. The Mixed Drug Use group was similar to the Heroin Only Users with age, front/back loading, and sharing cotton significantly associated with HIV infection. These differences became apparent only when neighborhood of residence was included in models run using GEE. The type of drug injected was associated with distinct behavioral risks. Risks specific to Stimulant Only Users appeared related to direct syringe sharing. The risks specific to the other two groups are common to the process of sharing drugs in preparation to injecting. Across the board, IDUs could profit from prevention education that emphasizes both access to clean syringes and preparing and apportioning drug with these clean syringes. However, attention to neighborhood differences might improve the intervention impact for injectors who favor different drugs.
HHH Fellow: Berna Ulu&ggrave;, Turkey, 1995-1996
Kaymak SU, Demir B, Sentźrk S, et al.
Neurocognitive Functions In Patients With First-Episode Major Depressive Disorders. European Archives of Psychiatry and Clinical Neuroscience. 2009 Sep 12. [Epub ahead of print]
The aim of this study was to determine whether there was any relationship between hippocampal volume, and glucocorticoid regulation, and cognitive dysfunctions in drug-na•ve major depressive disorder (MDD) patients during their first episode. Twenty drug-free female MDD patients in their first episode and 15 healthy females as control subjects were included in the study. All subjects underwent 3.0 Tesla (T) magnetic resonance imaging (MRI), comprehensive neuropsychological testing and dexamethasone suppression tests (DST). The volumes of the right and left hippocampus of the patients were found to be significantly smaller than those of the controls. Patients were found to have significantly lower scores on measures of attention, working memory, psychomotor speed, executive functions, and visual and verbal memory fields. The performance of the patients only in the recollection memory and memory of reward-associated rules were positively correlated with hippocampal volumes. The volumes of the left and right hippocampus did not correlate with basal or post-dexamethasone cortisol levels. Our findings indicate that depressed patients have smaller hippocampi even in the earlier phase of their illness. Further research efforts are needed to explain the mechanisms that are responsible for the small hippocampus in depressed patients.
PMID: 19756819 [PubMed - as supplied by publisher]
Ertugrul A, Volkan-Salanci B, Basar K, et al.
The Effect Of Clozapine On Regional Cerebral Blood Flow And Brain Metabolite Ratios In Schizophrenia: Relationship With Treatment Response. Psychiatry Research. 2009 Nov 30;174(2):121-9. Epub 2009 Oct 17.
The purpose of this study was to investigate the effect of clozapine on regional cerebral blood flow (rCBF) and its relationship with response to treatment. In addition, the authors aimed to study the influence of clozapine on proton magnetic resonance spectroscopy ((1)H-MRS) findings in the dorsolateral prefrontal cortex (DLPFC) in a subgroup of patients. Psychopathology, neurocognitive functioning, and SPECT imaging of 22 patients were assessed at the baseline and 8 weeks after the initiation of clozapine treatment. In 10 of these patients intermediate-echo (TE: 135 ms) single-voxel (1)H-MRS was also performed at the baseline and after 8 weeks. Clozapine treatment increased the right frontal (superior and medial)/caudate perfusion ratio in the whole group, while it increased bilateral frontal (superior and medial)/caudate perfusion ratios in treatment responders. In addition, percentage changes in left and right frontal (superior and medial)/caudate perfusion ratios compared to the baseline were higher in treatment responders than in non-responders. The improvement in attention was related to the increase in percentage change in the right frontal (superior and medial)/caudate perfusion ratio, while the improvement in verbal fluency was related to the increase in percentage changes in both right and left frontal (superior and medial)/caudate perfusion ratios and to right frontal (superior and medial)/thalamus perfusion. Baseline frontal (superior and medial)/thalamus perfusion could explain 32% of the variability of percentage improvements in psychopathology. (1)H-MRS showed that the baseline PANSS general psychopathology score was inversely correlated with the baseline NAA/Cre ratio. An increased NAA/Cre ratio in DLPFC after 8 weeks of clozapine treatment was also revealed by (1)H-MRS. Our SPECT imaging results suggest the presence of an imbalance in fronto-striato-thalamic circuitry that changes with clozapine, especially in the responders, while (1)H-MRS results indicate a supportive effect of clozapine on neuronal integrity.
PMID: 19837567 [PubMed - in process]
Otiashvili D, Zabransky T, Kirtadze I, et al.
- Tomas Zabransky, Czech Republic, 2003-2004
- David Otiashvili, Georgia, 2003-2004
Why Do the Clients of Georgian Needle Exchange Programmes Inject Buprenorphine?
European Addiction Research. 2009 Nov 2;16(1):1-8. [Epub ahead of print]
The aim of the study was to understand the prevalence and patterns of the non-medical injecting use of buprenorphine among drug injectors in Georgia. A self-administered questionnaire was distributed among injecting drug users enrolled in Georgian needle exchange programmes. The questions covered topics related to drug use career, patterns (frequency, history, dosage) and reasons for the use of buprenorphine. Pharmaceutical buprenorphine in the form of Subutex(R) was the most commonly injected drug in terms of lifetime (95.5%) and last-month (75%) prevalence of use. 48% of those study participants who had injected Subutex at some point reported having used it to cope with withdrawal or to give up other opioids. 90.5% of Subutex injectors used 1-2 mg as a single dose, and the mean frequency of its injection was 6 times per month. 75% of Subutex injectors had used 3 or more types of illegal drugs during the last 30 days. While widely misused by Georgian drug injectors, Subutex is neither the principal nor the favourite drug, and it is rather used as self-treatment. The authors consider the introduction of buprenorphine maintenance treatment to be a promising effective measure to decrease its non-medical and illegal use.