Clinical correlates and symptom patterns of anxious depression among patients with major depressive disorder in STAR*D

Fava, Maurizio; Alpert, Jonathan E.; Carmin, Cheryl N.; Wisniewski, Stephen R.; Trivedi, Madhukar H.; Biggs, Melanie M.; Shores-Wilson, Kathy; Morgan, D. K.; Schwartz, Terry Ann; Balasubramani, Goundappa K.; Rush, A. John

doi:10.1017/s0033291704002612

Cited by 341 publications

(291 citation statements)

References 30 publications

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“…We observed no genotype-dependent differences in sex, age, diagnostic subgroup (unipolar, bipolar, and psychotic), illness duration, number of previous depressive episodes, number of former hospitalizations, duration of current episode, chronic depression (current episode lasting X2 years), anxious depression (baseline HAM-D anxiety/ somatization factor score X7, Fava et al, 2004), HAM-D score at inclusion, plasma drug levels (corrected for age, gender, drug dosage, and body weight) of mirtazapine (n ¼ 89), trimipramine (n ¼ 62), venlafaxine (n ¼ 57), citalopram (n ¼ 49), and paroxetine (n ¼ 23) at week 5, and comedication with mood stabilizers, antipsychotics, or benzodiazepines at week 5. However, we found a nominally significant effect on age of onset for GRIK4 rs12800734, with AG heterozygotes suffering from their first depressive episode earlier in life (p ¼ 0.044).…”

Section: Association With Demographic Disease-related Variables Andmentioning

confidence: 68%

Polymorphisms in GRIK4, HTR2A, and FKBP5 Show Interactive Effects in Predicting Remission to Antidepressant Treatment

Horstmann

Lucae

Menke

et al. 2009

Neuropsychopharmacol

173

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Single-nucleotide polymorphisms (SNPs) in the FKBP5, GRIK4, and HTR2A genes have been shown to be associated with response to citalopram treatment in the STAR*D sample, but only associations with FKBP5 have so far been tested in the Munich Antidepressant Response Signature (MARS) project. Response and remission of depressive symptoms after 5 weeks of antidepressant treatment were tested against 82 GRIK4 and 37 HTR2A SNPs. Association analysis was conducted in about 300 depressed patients from the MARS project, 10% of whom had bipolar disorder. The most predictive SNPs from these two genes and rs1360780 in FKBP5 were then genotyped in a total of 387 German depressed in-patients to analyze potential additive and interactive effects of these variants. We could not replicate previous findings of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study in our sample. Although not statistically significant, the effect for the best GRIK4 SNP of STAR*D (rs1954787, p ¼ 0.076, p corrected ¼ 0.98) seemed to be in the same direction. On the other hand, the nominally significant association with the top HTR2A SNPs of STAR*D (rs7997012, allelic, p ¼ 0.043, p corrected ¼ 0.62) was with the opposite risk allele. The GRIK4 SNP (rs12800734, genotypic, p ¼ 0.0019, p corrected ¼ 0.12) and the HTR2A SNP (rs17288723, genotypic, p ¼ 0.0011, p corrected ¼ 0.02), which showed the strongest association with remission in our sample, had not been reported previously. Associations across all genetic markers within the GRIK4 (genotypic, p ¼ 0.022) or HTR2A (genotypic, p ¼ 0.012) locus using the Fisher's product method (FPM) were also significant. In all 374 patients, the best predictive model included a main effect for GRIK4 rs12800734 and two significant interactions between GRIK4 rs12800734 and FKBP5 rs1360780, and GRIK4 rs12800734 and HTR2A rs17288723. This three SNP model explained 13.1% of the variance for remission after 5 weeks (p ¼ 0.00051 for the model). Analyzing a sub-sample of 194 patients, plasma ACTH (p ¼ 0.002) and cortisol (p ¼ 0.021) responses of rs12800734 GG (GRIK4) carriers, who also showed favorable treatment response, were significantly lower in the second combined dexamethasone (dex)/corticotrophin-releasing hormone (CRH) test before discharge compared with the other two genotype groups. Despite large differences in ethnicity and design compared with the STAR*D study, our results from the MARS study further support both independent and interactive involvement of GRIK4, HTR2A and FKBP5 in antidepressant treatment response.

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Section: Association With Demographic Disease-related Variables Andmentioning

confidence: 68%

Polymorphisms in GRIK4, HTR2A, and FKBP5 Show Interactive Effects in Predicting Remission to Antidepressant Treatment

Horstmann

Lucae

Menke

et al. 2009

Neuropsychopharmacol

173

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“…likely represent a common and valid subtype of mood disorder (Fava et al, 2004(Fava et al, , 2006 and are less likely to achieve remission with standard SSRIs (Trivedi et al, 2006). One intriguing mechanism that could explain riluzole's anxiolytic efficacy is evidence that at higher concentrations, riluzole strongly potentiated postsynaptic GABA A receptor function in cultured hippocampal neurons (He et al, 2002).…”

Section: Riluzole (Major Depressive Disorder and Bipolar Depression)mentioning

confidence: 99%

Novel Drugs and Therapeutic Targets for Severe Mood Disorders

Mathew

Manji

Charney

2008

Neuropsychopharmacol

207

140

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Monoaminergic-based drugs remain the primary focus of pharmaceutical industry drug discovery efforts for mood disorders, despite serious limitations regarding their ability to achieve remission. The quest for novel therapies for unipolar depression and bipolar disorder has generally centered on two complementary approaches: (1) understanding the presumed therapeutically relevant biochemical targets of currently available medications, and using that knowledge to design new drugs directed at both direct biochemical targets and downstream targets that are regulated by chronic drug administration; and (2) developing pathophysiological models of the illness to design therapeutics to attenuate or prevent those pathological processes. This review describes several promising drugs and drug targets for mood disorders using one or both of these approaches. Agents interacting with non-catecholamine neurotransmitter systems with particular promise for unipolar and bipolar depression include excitatory amino acid neurotransmitter modulators (eg, riluzole, N-methyl-D-aspartate antagonists, and AMPA receptor potentiators) and neuropeptide antagonists (targeting corticotropin releasing factor-1 and neurokinin receptors). Potential antidepressant and mood-stabilizing agents targeting common intracellular pathways of known monoaminergic agents and lithium/mood stabilizers are also reviewed, such as neurotrophic factors, extracellular receptor-coupled kinase (ERK) mitogen-activated protein (MAP) kinase and the bcl-2 family of proteins, and inhibitors of phosphodiesterase, glycogen synthase kinase-3, and protein kinase C. A major thrust of drug discovery in mood disorders will continue efforts to identify agents with rapid and sustained onsets of action (such as intravenous administration of ketamine), as well as identify drugs used routinely in non-psychiatric diseases for their antidepressant and mood-stabilizing properties.

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“…Indeed, it has been estimated that 40-50% of MDD patients, whether inpatient or outpatient, have at least one comorbid anxiety disorder (Fava et al, 2006;Wiethoff et al, 2010). Clinically, compared to nonanxious depressive patients, anxious depression presents with more frequent depressive episodes, more severe symptoms and side-effects, and patients exhibit worse outcomes and treatment responses (Fava et al, 2004(Fava et al, , 2008.…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, anxious depressive patients take twice as long to recover from depressive episodes and are more prone to physical discomfort, depersonalization, derealization, and a higher proportion of suicide attempts than patients without anxiety symptoms (Fava et al, 2004;Goldberg, 2014).…”

Section: Introductionmentioning

confidence: 99%

Cortical thickness and subcortical structure volume abnormalities in patients with major depression with and without anxious symptoms

et al. 2017

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Clinical correlates and symptom patterns of anxious depression among patients with major depressive disorder in STAR*D

Abstract: This study supports specific clinical and sociodemographic correlates of MDD associated with high levels of anxiety (anxious depression).

Cited by 341 publications

References 30 publications

Polymorphisms in GRIK4, HTR2A, and FKBP5 Show Interactive Effects in Predicting Remission to Antidepressant Treatment

Polymorphisms in GRIK4, HTR2A, and FKBP5 Show Interactive Effects in Predicting Remission to Antidepressant Treatment

Novel Drugs and Therapeutic Targets for Severe Mood Disorders

Cortical thickness and subcortical structure volume abnormalities in patients with major depression with and without anxious symptoms

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