Sneha Narasimhan

Pharmacogenetics of antidepressant drugs: current clinical practice and future directions

While antidepressants are widely used to treat mood and anxiety disorders, only half of the patients will respond to antidepressant treatment and only one-third of patients experience a full remission of symptoms. The identification of genetic biomarkers that predict antidepressant-treatment response can improve current clinical practice. This is an emerging field known as pharmacogenetics, which comprises of genetic studies on both the pharmacokinetics and pharmacodynamics of treatment response. Recent studies on antidepressant-treatment response have focused on both aspects of pharmacogenetics research, identifying new candidate genes that may predict better treatment response for patients. This paper reviews recent findings on the pharmacogenetics of antidepressant drugs and future clinical applications. Ultimately, these studies should lead to the use of genetic testing to guide the use of antidepressants in clinical practice.

Pathological Tau Strains from Human Brains Recapitulate the Diversity of Tauopathies in Nontransgenic Mouse Brain

Pathological tau aggregates occur in Alzheimers disease (AD) and other neurodegenerative tauopathies. It is not clearly understood why tauopathies vary greatly in the neuroanatomical and histopathological patterns of tau aggregation, which contribute to clinical heterogeneity in these disorders. Recent studies have shown that tau aggregates may form distinct structural conformations, known as tau strains. Here, we developed a novel model to test the hypothesis that cell-to-cell transmission of different tau strains occurs in nontransgenic (non-Tg) mice, and to investigate whether there are strain-specific differences in the pattern of tau transmission. By injecting pathological tau extracted from postmortem brains of AD (AD-tau), progressive supranuclear palsy (PSP-tau), and corticobasal degeneration (CBD-tau) patients into different brain regions of female non-Tg mice, we demonstrated the induction and propagation of endogenous mouse tau aggregates. Specifically, we identified differences in tau strain potency between AD-tau, CBD-tau, and PSP-tau in non-Tg mice. Moreover, differences in cell-type specificity of tau aggregate transmission were observed between tau strains such that only PSP-tau and CBD-tau strains induce astroglial and oligodendroglial tau inclusions, recapitulating the diversity of neuropathology in human tauopathies. Furthermore, we demonstrated that the neuronal connectome, but not the tau strain, determines which brain regions develop tau pathology. Finally, CBD-tau- and PSP-tau-injected mice showed spatiotemporal transmission of glial tau pathology, suggesting glial tau transmission contributes to the progression of tauopathies. Together, our data suggest that different tau strains determine seeding potency and cell-type specificity of tau aggregation that underlie the diversity of human tauopathies. SIGNIFICANCE STATEMENT Tauopathies show great clinical and neuropathological heterogeneity, despite the fact that tau aggregates in each disease. This heterogeneity could be due to tau aggregates forming distinct structural conformations, or strains. We now report the development of a sporadic tauopathy model to study human tau strains by intracerebrally injecting nontransgenic mice with pathological tau enriched from human tauopathy brains. We show human tau strains seed different types and cellular distributions of tau neuropathology in our model that recapitulate the heterogeneity seen in these human diseases.

Amyloid-β plaques enhance Alzheimer's brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation

Alzheimers disease (AD) is characterized by extracellular amyloid-β (Aβ) plaques and intracellular tau inclusions. However, the exact mechanistic link between these two AD lesions remains enigmatic. Through injection of human AD-brain-derived pathological tau (AD-tau) into Aβ plaque–bearing mouse models that do not overexpress tau, we recapitulated the formation of three major types of AD-relevant tau pathologies: tau aggregates in dystrophic neurites surrounding Aβ plaques (NP tau), AD-like neurofibrillary tangles (NFTs) and neuropil threads (NTs). These distinct tau pathologies have different temporal onsets and functional consequences on neural activity and behavior. Notably, we found that Aβ plaques created a unique environment that facilitated the rapid amplification of proteopathic AD-tau seeds into large tau aggregates, initially appearing as NP tau, which was followed by the formation and spread of NFTs and NTs, likely through secondary seeding events. Our study provides insights into a new multistep mechanism underlying Aβ plaque–associated tau pathogenesis.

Functional genetic variants in the vesicular monoamine transporter 1 modulate emotion processing

Emotional behavior is in part heritable and often disrupted in psychopathology. Identification of specific genetic variants that drive this heritability may provide important new insight into molecular and neurobiological mechanisms involved in emotionality. Our results demonstrate that the presynaptic vesicular monoamine transporter 1 (VMAT1) Thr136Ile (rs1390938) polymorphism is functional in vitro, with the Ile allele leading to increased monoamine transport into presynaptic vesicles. Moreover, we show that the Thr136Ile variant predicts differential responses in emotional brain circuits consistent with its effects in vitro. Lastly, deep sequencing of bipolar disorder (BPD) patients and controls identified several rare novel VMAT1 variants. The variant Phe84Ser was only present in individuals with BPD and leads to marked increase monoamine transport in vitro. Taken together, our data show that VMAT1 polymorphisms influence monoamine signaling, the functional response of emotional brain circuits and risk for psychopathology.

Neuronal calcium sensor-1 and cocaine addiction: a genetic association study in African-Americans and European Americans.

Genes involved in drug reward pathways are plausible candidates for susceptibility to substance use disorders. Given the prominent role of dopamine in drug reward, dopamine receptor-interacting proteins (DRIPs) such as the neuronal calcium sensor-1 (NCS-1) protein have been hypothesized to play a role in the pathophysiology of cocaine addiction (CA). In this study, we investigated whether genetic variants in the NCS-1 gene confer risk to CA. We genotyped 8 SNPs (rs4837479, rs7849345, rs3824544, rs10819611, rs947513, rs2277200, rs7873936 and rs1342043) in our discovery sample (cases n = 796, controls n = 416) of African descent. Confirmation of associated or trending SNPs (rs7849345, rs10819611, rs1342043) was attempted using a replication sample of African American (AA) ethnicity (cases n = 335, controls n = 336) and European-American (EA) ancestry (cases n = 336, controls n = 656). Secondary sex specific analysis was also carried out for each SNP in both AA and EA individuals. Genotyping of the discovery cohort showed significant genotypic (p = 0.0005, corrected q-value) as well as allelic (p = 0.005, corrected q-value) associations of rs1342043 with CA in AAs; however, this marker could not be confirmed in either the AA or EA replication sample. Combined analysis of all AA samples (n = 1883) for rs1342043 showed a significant association with CA (genotypic p = 0.0001, allelic p = 0.002) with a gender specific effect for males (allelic p = 0.005, genotypic p = 0.0003). Our data suggest that genetic variants in the NCS-1 gene contribute to susceptibility of CA in individuals of African descent.

Variation in the catechol-O-methyltransferase (COMT) gene and treatment response to venlafaxine XR in generalized anxiety disorder

Antidepressant drugs are the preferred choice for the treatment of generalized anxiety disorder (GAD). However, the choice of pharmacotherapy is determined on a trial-and-error basis, as the underlying mechanisms of treatment response are unknown. We examined whether the COMT gene, which has been known to play a role in antidepressant treatment response in major depressive disorder (MDD), has a pharmacogenetic effect in antidepressant treatment response in GAD. In our study, 156 patients diagnosed with GAD received venlafaxine XR treatment as part of an 18-month relapse prevention study. Genotypes were obtained for the COMT functional variant rs4680 (Val158Met) for all patients; however, pharmacogenetic analysis was only conducted for the European American population (n=112). We found no significant association between our primary Hamilton Anxiety Scale outcome measure and rs4680. However, we did find a nominally significant allelic association between this variant and a secondary treatment outcome measure (CGI-I) in our European American population (n=112). Furthermore, we show a slight dominant effect of the A-allele with the CGI-I measure in the European American population indicating a possible pharmacogenetic role of rs4680 in antidepressant treatment outcome in GAD. Further studies in a larger population are needed to confirm this effect.

Lack of influence of DAT1 and DRD2 gene variants on antidepressant response in generalized anxiety disorder.

Although antidepressant drugs are used as first‐line intervention to treat patients with generalized anxiety disorder (GAD), only one‐third of patients respond positively to treatment. In our study, we investigated whether functional genetic polymorphisms in the dopamine active transporter 1 (DAT1) and dopamine receptor D2 (DRD2) may play a role in antidepressant treatment response in GAD.

Association analysis between the Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene and treatment response to venlafaxine XR in generalized anxiety disorder

While antidepressant drugs are used to treat generalized anxiety disorder (GAD), patients vary greatly in their treatment response. Evidence shows genetic factors may play a role in treatment response in GAD. We examined whether the BDNF gene, which has been shown to play a role in antidepressant treatment response in major depressive disorder (MDD), also has an effect in GAD. In our study, 155 patients diagnosed with GAD received venlafaxine XR treatment as part of an 18-month relapse prevention study. Genotypes were obtained for the BDNF functional variant rs6265 (Val66Met) for the entire sample (n=155); however, only the European American (EA) population was considered (n=111) for pharmacogenetic analysis. We did not find a significant association between rs6265 and antidepressant treatment response in our GAD population. Future studies in larger populations will need to be conducted to further elucidate the pharmacogenetic role of this variant in anxiety disorders.

Genetic polymorphisms in the PACAP and PAC1 receptor genes and treatment response to venlafaxine XR in generalized anxiety disorder

The pituitary adenylate cyclase-activating peptide (PACAP) and its receptor (PAC1) are involved in stress response and anxiety. Genotypes for PACAP/PAC1 were examined for effects on treatment response to venlafaxine XR in generalized anxiety disorder. The Asp54Gly (rs2856966) variant in the PACAP gene was associated with better treatment outcome.

Association analysis between the 5-HTTLPR polymorphism in the SLC6A4 gene and generalized anxiety disorder.

Departments of Psychiatry, Psychiatric Pharmacogenetics Laboratory, Psychiatry, Center for Neurobiology and Behavior, Psychiatry, Mood and Anxiety Disorders Section, School of Medicine and Department of Psychology, Center for Cognitive Neuroscience, University of Pennsylvania, Philadelphia, Pennsylvania, USA Correspondence to Falk W. Lohoff, MD, University of Pennsylvania, 125 S. 31st Street, Room 2210, Philadelphia, PA 19104, USA Tel: + 1 215 5734582; fax: + 1 215 5732041; e-mail: lohoff@mail.med.upenn.edu