Journal of Psychiatric Research

Editorial Board and Publication Information

2012-05-01

Neurobiological correlates of illness progression in the recurrent affective disorders

Robert M. Post, Jaclyn Fleming, Flavio Kapczinski — 2012-03-26

Abstract: Some clinical aspects of affective illness progression, such as episode-, stress-, and substance-induced sensitization, have been well documented in the literature, but others have received less attention. These include cognitive deficits, treatment-refractoriness, and neurobiological correlates of illness progression, which are the primary focus of this paper. We review the evidence that cognitive dysfunction, treatment resistance, medical comorbidities, and neurobiological abnormalities increase as a function of the number of prior episodes or duration of illness in the recurrent unipolar and bipolar disorders. Substantial evidence supports the view that cognitive dysfunction and vulnerability to a diagnosis of dementia in old age increases as a function of number of prior mood episodes as does non-response to many therapeutic interventions as well as naturalistic treatment. Neurobiological abnormalities that correlate with the number of mood episodes or duration of illness include: anatomical, functional, and biochemical deficits in the prefrontal cortex and hippocampus, as well as amygdala hyperactivity and cortisol hyper-secretion. Some neurotrophic factors and inflammatory markers may also change with greater illness burden. Causality cannot be inferred from these correlative relationships. Nonetheless, given the potentially grave consequences of episode recurrence and progression for morbidity and treatment non-responsiveness, it is clinically wise to assume episodes are causing some of the progressive cognitive and neurobiological abnormalities. As such, earlier and more sustained long-term prophylaxis to attempt to reduce these adverse outcomes is indicated.

Facing depression with botulinum toxin: A randomized controlled trial

2012-02-27

Abstract: Positive effects on mood have been observed in subjects who underwent treatment of glabellar frown lines with botulinum toxin and, in an open case series, depression remitted or improved after such treatment. Using a randomized double-blind placebo-controlled trial design we assessed botulinum toxin injection to the glabellar region as an adjunctive treatment of major depression.Thirty patients were randomly assigned to a verum (onabotulinumtoxinA, n = 15) or placebo (saline, n = 15) group. The primary end point was change in the 17-item version of the Hamilton Depression Rating Scale six weeks after treatment compared to baseline.The verum and the placebo groups did not differ significantly in any of the collected baseline characteristics. Throughout the sixteen-week follow-up period there was a significant improvement in depressive symptoms in the verum group compared to the placebo group as measured by the Hamilton Depression Rating Scale (F(6,168) = 5.76, p < 0.001, η2 = 0.17). Six weeks after a single treatment scores of onabotulinumtoxinA recipients were reduced on average by 47.1% and by 9.2% in placebo-treated participants (F(1,28) = 12.30, p = 0.002, η2 = 0.31, d = 1.28). The effect size was even larger at the end of the study (d = 1.80). Treatment-dependent clinical improvement was also reflected in the Beck Depression Inventory, and in the Clinical Global Impressions Scale.This study shows that a single treatment of the glabellar region with botulinum toxin may shortly accomplish a strong and sustained alleviation of depression in patients, who did not improve sufficiently on previous medication. It supports the concept, that the facial musculature not only expresses, but also regulates mood states.

Risk propensity and health risk behaviors in U.S. army soldiers with and without psychological disturbances across the deployment cycle

2012-02-06

Abstract: Anecdotal and preliminary evidence suggests that Soldiers returning from a combat deployment engage in an increased number of health risk behaviors. Three potential factors driving this change were examined in this study; posttraumatic stress disorder (PTSD), concussion and traumatic brain injury (TBI), and perceived invincibility. We studied members of a combat arms brigade one month prior to a deployment to Iraq and approximately one month after their return (N = 319). Participants anonymously completed surveys characterizing attitudes about risk, risk propensity, invincibility, engagement in health risk behaviors, and personality. Using standardized screening instruments, participants were categorized with respect to PTSD and probable TBI. Results suggest that Soldiers engage in more alcohol use and reckless driving behaviors post-deployment. These changes were exaggerated in those who screened positive for PTSD. Perception of one’s invincibility and survival skills increased post-deployment thus suggesting that participants felt less susceptible to adverse consequences and more adept at surviving dangerous situations. This study provides documentation of the pattern of health behavior in Soldiers engaged in the deployment cycle. Our findings suggest increases in the number of risks Soldiers’ engage in post-deployment are not limited to those with PTSD symptomtotology. This study has implications for not only adjustment to life post-deployment at the individual level but also operational readiness.

Pre-schoolers suffering from psychiatric disorders show increased cortisol secretion and poor sleep compared to healthy controls

2012-02-10

Abstract: Background: Various studies of child cortisol secretion and sleep show a close association between poor sleep, deterioration of the HPA axis and unfavorable psychological functioning. However, there is little evidence as to whether these associations are clearly present in pre-school children suffering from psychiatric disorders.Method: A total of 30 pre-schoolers suffering from psychiatric disorders (anxiety, adjustment disorders, emotional and attachment disorder; hyperactivity or oppositional disorder) and 35 healthy controls took part in the study. Saliva cortisol secretion was assessed both at baseline and under challenge conditions. Sleep was assessed via activity monitoring for seven consecutive days and nights, using a digital movement-measuring instrument. Parents and teachers completed questionnaires assessing children's cognitive, emotional and social functioning. The Berkeley Puppet Interview provided child-based reports of cognitive–emotional processes.Results: Compared to healthy controls, children suffering from psychiatric disorders had much higher cortisol secretion both at baseline and under challenge conditions. Sleep was also more disturbed, and parents and teachers rated children suffering from psychiatric disorders as cognitively, emotionally and behaviorally more impaired, relative to healthy controls. Children with psychiatric disorders reported being more bullied and victimized.Conclusions: In five-year old children the presence of psychiatric disorders is reflected not only at psychological, social and behavioral, but also at neuroendocrine and sleep-related levels. It is likely that these children remain at increased risk for suffering from psychiatric difficulties later in life.

Relationship between childhood adversity and clinical and cognitive features in schizophrenia

2012-02-13

Abstract: Childhood adversity is associated with elevated risk for a wide range of adult psychiatric disorders, and has significant and sustained negative effects on adult behavioural and social functioning. Elevated rates of childhood adversity have been reported for people with a diagnosis of schizophrenia. The aim of the present study was to assess rates of retrospectively reported childhood adversity among adults with schizophrenia and to examine the relationship between childhood adversity and clinical and cognitive features. Data were available for 408 schizophrenia participants and 267 healthy control participants recruited through the Australian Schizophrenia Research Bank (ASRB). History of childhood adversity was obtained using the Childhood Adversity Questionnaire (CAQ). A five-factor solution was identified from the CAQ. Schizophrenia participants reported experiencing more childhood adversities than controls. In both groups, those reporting childhood adversity were more likely to be female and older. Among participants with schizophrenia, positive symptom severity and fewer years of education were associated with childhood adversity. Lower IQ scores and personality traits were associated with reporting a greater number of childhood adversities and with adversity sub-types of abusive, neglectful and dysfunctional parenting. The rate of childhood adversity reported in this sample was high which suggests greater exposure to adverse childhood events among participants with schizophrenia in comparison with healthy controls. We identified unique groups amongst CAQ items that provided a salient framework from which to investigate the connection between childhood adversity and clinical and cognitive features.

Do depression and anxiety converge or diverge in their association with suicidality?

2012-02-17

Abstract: Depressive disorders have been strongly linked to suicidality, but the association with anxiety disorders is less well established. This exploratory study aims to examine whether anxiety and depressive disorders are both independent risk factors for suicidal ideation and attempted suicide, and additionally examined the role of specific clinical characteristics (disorder type, severity, duration, onset age) in suicidality. Data are from 1693 persons with a current (6-month) CIDI based depressive or anxiety disorder and 644 healthy controls participating in the baseline measurement of the Netherlands Study of Depression and Anxiety, which is an existing dataset. Suicidal ideation in the week prior to baseline and attempted suicide ever in life were assessed. Results showed that compared to persons with only an anxiety disorder, persons with a depressive disorder were at significantly higher risk to have current suicidal ideation or a history of attempted suicide. When examining the association between type of disorder and suicidality the odds ratio for MDD was significantly higher than those for the separate anxiety disorders. Although depression and anxiety severity were univariate risk indicators for suicidal ideation and attempted suicide, only depression severity remained a risk indicator for suicidal ideation and attempted suicide in multivariate analyses. Additional risk indicators were an early age at disorder onset for both suicidal ideation and attempted suicide, male gender for suicidal ideation and lower education for attempted suicide. These findings suggest that although anxiety and depression tend to converge in many important areas, they appear to diverge with respect to suicidality.

Does anxiety increase impulsivity in patients with bipolar disorder or major depressive disorder?

2012-02-13

Abstract: The objective of this study was to examine whether anxiety increases impulsivity among patients with bipolar disorder (BPD) and major depressive disorder (MDD). Subjects comprised 205 BPD (mean age ± SD 36.6 ± 11.5 y; 29.3% males) and 105 with MDD (mean age ± SD 38 ± 13.1 y; 29.5% males) diagnosed using the DSM-IV-SCID. Impulsivity was assessed with the Barratt Impulsivity Scale and anxiety with the Hamilton Anxiety Rating Scale. Comorbid anxiety disorders were present in 58.9% of the BPD and 29.1% of MDD. BPD were significantly more impulsive than MDD (p < 0.001), and both BPD and MDD subjects showed significantly higher impulsivity when anxiety was present either as a comorbidity (p = 0.010) or as a symptom (p = 0.011). Impulsivity rose more rapidly with increasing anxiety symptoms in MDD than in BPD. The presence of anxiety, either as a comorbid disorder or as current anxiety symptoms, is associated with higher impulsivity in subjects with either BPD or MDD.

T-817MA, a novel neurotrophic agent, ameliorates loss of GABAergic parvalbumin-positive neurons and sensorimotor gating deficits in rats transiently exposed to MK-801 in the neonatal period

2012-02-20

Abstract: T-817MA [1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}azetidin-3-ol maleate] is a newly synthesized neuroprotective agent for the treatment of psychiatric disorders characterized by cognitive disturbances, such as Alzheimer’s disease. Cognitive impairment has also been suggested to be a cardinal feature of schizophrenia. We sought to determine whether T-817MA would ameliorate sensorimotor gating deficits and loss of parvalbumin (PV)-positive γ-aminobutyric acid (GABA) neurons in the brain of rats transiently exposed to MK-801, an N-methyl-d-aspartate receptor blocker, in the neonatal stage, as an animal model of schizophrenia. Prepulse inhibition (PPI) was examined in rats treated neonatally with MK-801 (postnatal day; PD 7–10, 0.2 mg/kg/day, s.c.) or vehicle at PD 35 and PD 63. The number of PV-positive GABAergic neurons in the medial prefrontal cortex (mPFC) and the hippocampus was measured after the behavioral assessments. T-817MA (10 or 20 mg/kg) or vehicle was administered for 14 days (on PD 49–62). Administration of T-817MA at 20 mg/kg, but not 10 mg/kg, ameliorated PPI deficits and completely reversed the decrease in the number of PV-positive GABAergic neurons in rats given MK-801. These results indicate that T-817MA may provide a novel therapeutic approach for the treatment of cognitive deficits of schizophrenia.

Mutation analysis of the NRXN1 gene in a Chinese autism cohort

2012-03-14

Abstract: Autism is a brain developmental disorder characterized by impaired social interaction and communication, as well as restricted and repetitive behaviors. The neurexin-1(NRXN1) gene mapped on chromosome 2p16.3 encodes neurexin, a cell adhesion molecule and receptor in the vertebrate nervous system. Rare de novo alterations and copy number variations (CNVs) suggested neurexin-1 as a candidate gene for the pathogenesis of autism, but data on the gene mutation of neurexin-1 in Chinese Han population with autism are limited. By direct sequencing, we analyzed the entire coding regions and associated splice junctions of neurexin-1 in 313 Chinese autism patients. For exons in which non-synonymous variants were identified, sequencing was performed in 500 healthy controls. We identified 22 variants in the neurexin-1 coding regions, including 7 missense variants, 3 deletions, and 12 synonymous mutations. Among them, 3 missense and 3 synonymous variants were not reported in the dbSNP database and absent in 500 control subjects; whereas 4 missense variants, 3 deletions and 3 synonymous mutations were not reported in the dbSNP database but were identified in the control subjects. However, there is no significant association of these mutations with autism risk. Interestingly, there was a statistically significant association of neurexin-1 SNP P300P (rs2303298) with risk of autism (26.2% vs. 13.8%; χ2 = 22.487; p = 3.45E-006; OR = 2.152 (1.559–2.970)). Our data suggest a possible association of neurexin-1 with autism risk in Chinese Han population, warranting further large-scale study on this gene.

Vorinostat, a histone deacetylase inhibitor, facilitates fear extinction and enhances expression of the hippocampal NR2B-containing NMDA receptor gene

2012-02-27

Abstract: Histone acetylation, which alters the compact chromatin structure and changes the accessibility of DNA to regulatory proteins, is emerging as a fundamental mechanism for regulating gene expression. Histone deacetylase (HDAC) inhibitors increase histone acetylation and enhance fear extinction. In this study, we examined whether vorinostat, an HDAC inhibitor, facilitates fear extinction, using a contextual fear conditioning (FC) paradigm, in Sprague-Dawley rats. We found that vorinostat facilitated fear extinction. Next, the levels of global acetylated histone H3 and H4 were measured by Western blotting. We also assessed the effect of vorinostat on the hippocampal levels of NMDA receptor mRNA by real-time quantitative PCR (RT-PCR) and protein by Western blotting. 2 h after vorinostat administration, the levels acetylated histones and NR2B mRNA, but not NR1 or NR2A mRNA, were elevated in the hippocampus. The NR2B protein level was elevated 4 h after vorinostat administration. Last, we investigated the levels of acetylated histones and phospho-CREB (p-CREB) binding at the promoter of the NR2B gene using the chromatin immunoprecipitation (ChIP) assay followed by RT-PCR. The ChIP assay revealed increases in the levels of acetylated histones and they were accompanied by enhanced binding of p-CREB to its binding site at the promoter of the NR2B gene 2 h after vorinostat administration. These findings suggest that vorinostat increases the expression of NR2B in the hippocampus by enhancing histone acetylation, and this process may be implicated in fear extinction.

The state effect of depressive and anxiety disorders on big five personality traits

2012-02-20

Abstract: Background: Neuroticism and extraversion are affected by depressive disorder state. Less is known about depressive state effects on conscientiousness, agreeableness and openness. Furthermore, state effects of anxiety disorders on personality have been far less studied than those of depressive disorder. Here, we aim to determine the extent of change in all five personality traits associated with the occurrence of or recovery from depressive and anxiety disorders.Methods: Using the Composite International Diagnostic Interview (CIDI) at baseline and two-year follow-up, respondents from the Netherlands Study of Depression and Anxiety (NESDA) were divided into four groups: unaffected at baseline and follow-up, occurrence, recovery, and affected at baseline and follow-up. Personality change (NEO-five factor inventory) was examined in the occurrence and recovery groups relative to the unaffected and affected groups, respectively. Analyses were repeated, differentiating between (specific) depressive and anxiety disorders.Results: We found small state effects of affective disorders on neuroticism, extraversion and conscientiousness. Corrected for each other, both depressive and anxiety disorders showed small state effects on neuroticism, but effects on extraversion and conscientiousness were mainly associated with depressive disorders.Conclusions: State effects were small. When assessing neuroticism, the presence of both depressive and anxiety disorders should be taken into account, as both may independently increase neuroticism scores. However, when assessing extraversion and conscientiousness, depressive disorders but not anxiety disorders are likely to be of influence. Agreeableness and openness are influenced by neither.

Emotion regulation and impulsivity in young adults

Liana R.N. Schreiber, Jon E. Grant, Brian L. Odlaug — 2012-03-05

Abstract: Past research has linked both emotion regulation and impulsivity with the development and maintenance of addictions. However, no research has investigated the relationship between emotion regulation and impulsivity within young adults. In the present study, we analyzed 194 young adults (27.8% female; 21.3 ± 3.32 years old; 91.8% single; 85.1% Caucasian), grouping them as low, average, or high emotionally dysregulated, and compared self-reported impulsivity, impulsive behaviors (such as alcohol and substance use and gambling) and cognitive impulsivity. We hypothesized that those with high levels of emotion dysregulation would score higher on self-reported and cognitive impulsivity, and report more impulsive behaviors. Analysis indicated that compared to low, the high emotion dysregulation group scored significantly higher on two self-report measures of impulsivity, harm avoidance, and cognitive reasoning. No significant differences were found between groups in impulsive behaviors and cognitive impulsivity. Overall, this study highlights the relationship between emotion dysregulation and impulsivity, suggesting that emotion regulation may be an important factor to consider when assessing individuals at a higher risk for developing an addiction.

Comparison of the course of substance use disorders among individuals with and without generalized anxiety disorder in a nationally representative sample

Jessica F. Magidson, Shang-Min Liu, C.W. Lejuez, Carlos Blanco — 2012-03-26

Abstract: Generalized anxiety disorder (GAD) and substance use disorders (SUDs) are highly comorbid, and GAD–SUD comorbidity is associated with a host of poor psychosocial outcomes, including higher rates of hospitalization, disability, functional impairment, and inferior GAD and SUD treatment outcomes. Despite the noted severity of this group and clinical implications, current research is limited in a few distinct ways; studies have rarely utilized a longitudinal design and non-treatment seeking individuals to examine how GAD comorbidity impacts SUD outcomes over time. The current study utilized a nationally representative sample of individuals in the U.S. assessed in the National Epidemiological Survey on Alcohol and Related Conditions (NESARC) at Wave 1 (2001–2002) and Wave 2 (2004–2005), comparing individuals who met criteria for both DSM-IV past year GAD and SUD (n = 286) and those who met criteria for past year SUD only without GAD (n = 5730) at Wave 1. Results indicated that GAD–SUD individuals were significantly more severe than the SUD only group across almost all outcomes assessed (with the exception of alcohol frequency); individuals with GAD–SUD had a more severe psychiatric history, worse health-related quality of life at both waves, greater incidence of new Axis I disorders, higher rates of treatment seeking, and greater self-reported drug use at the follow up. The current study is the first to compare individuals with SUD with and without comorbid GAD over time using a nationally representative sample. Findings further support the clinical severity of this group and suggest the need for GAD–SUD treatment options.

Apathy in currently nondepressed patients treated with a SSRI for a major depressive episode: Outcomes following randomized switch to either duloxetine or escitalopram

2012-03-14

Abstract: Apathy in the context of treated major depressive disorder (MDD) is a common but understudied symptom. This multicenter, double-blind, randomized study investigated whether switching from a selective serotonin reuptake inhibitor (SSRI) to a serotonin-norepinephrine reuptake inhibitor (SNRI), compared with switching to another SSRI, improved apathy symptoms in patients who had been treated with a SSRI for MDD for ≥3 months, were no longer depressed (Montgomery-Åsberg Depression Rating Scale [MADRS] total score ≤15), and continued to have apathy (Apathy Evaluation Scale – Clinician rated version [AES-C] total score >30). Following 8 weeks of treatment, both the duloxetine (SNRI, 244 patients) and escitalopram (SSRI, 239 patients) groups significantly improved from baseline on the AES-C total score (least squares mean change [standard error]: duloxetine −13.9 [0.54]; escitalopram −13.5 [0.54], both P < 0.001), and on the secondary apathy, depression, and functional outcomes. There were no significant differences between the two groups on any measure, including AES-C total score (least squares mean difference [95% confidence interval]: −0.4 [−1.87 to 1.10], P = 0.612; primary objective). There was a significant within-group improvement in apathy in the subgroup who received escitalopram before and during the study. There were few differences in safety between the two groups. This study did not support the hypothesis that switching from a SSRI to a SNRI has a beneficial effect on apathy symptoms. However, given the study limitations, it is possible that more specific targeting of the noradrenergic pathway would be of benefit.

The relationship between age of gambling onset and adolescent problematic gambling severity

2012-03-14

Abstract: The aim of this study was to characterize the association between problem gambling severity and multiple health, functioning and gambling variables in adolescents aged 13–18 stratified by age of gambling onset. Survey data in 1624 Connecticut high school students stratified by age of gambling onset (≤11 years vs. ≥ 12 years) were analyzed in descriptive analyses and in logistic regression models. Earlier age of onset was associated with problem gambling severity as indexed by a higher frequency of at-risk/problem gambling (ARPG). Most health, functioning and gambling measures were similarly associated with problem gambling severity in the earlier- and later-age-of-gambling-onset groups with the exception of participation in non-strategic forms of gambling, which was more strongly associated with ARPG in the earlier-onset (OR = 1.74, 95%CI = [1.26, 2.39]) as compared to later-onset (OR = 0.94, 95%CI = [0.60, 1.48]) group (Interaction OR = 1.91, 95%CI = [1.18, 3.26]). Post-hoc analysis revealed that earlier-onset ARPG was more strongly associated with multiple forms of non-strategic gambling including lottery (instant, traditional) and slot-machine gambling. The finding that problem gambling severity is more closely associated with multiple non-strategic forms of gambling amongst youth with earlier-onset gambling highlights the relevance of these types of youth gambling. The extent to which non-strategic forms of gambling may serve as a gateway to other forms of gambling or risk behaviors warrants additional study, and efforts targeting youth gambling should consider how best to address non-strategic gambling through education, prevention, treatment and policy efforts.

Contribution of orodental status to the intensity of orofacial tardive dyskinesia: An interdisciplinary and video-based assessment

2012-03-05

Abstract: Background: Tardive dyskinesia (TD) is a neurological motor complication eventually arising in one-third of patients chronically exposed to antipsychotic drugs. Some orodental peripheral factors have been reported to influence TD.Objective: To measure orodental factors such as temporomandibular joint function, static occlusal contacts, and denture condition, and attempt correlations with orofacial TD intensity.Methods: In this exploratory cross-sectional pilot study, 31 subjects between 30 and 75 years of age were divided in two groups displaying minimal to mild, or moderate to severe orofacial TD, respectively, and underwent a detailed oral, dental, and prosthetic evaluation to capture various aspects of oral health compared between the two groups. Blinded video-based TD ratings along a validated scale were obtained to compare dentulous and edentulous subjects, and contrast TD intensity in complete denture wearers with and without their own prostheses.Results: None of the factors examined tightly correlated with orofacial TD intensity. However, edentulism was associated with a higher median orofacial TD rating compared to the dentulous group (p = 0.001). Further, a significant intra-subject difference was observed in the edentulous subjects rated with their own complete dentures in place or not (p = 0.028), the dentures attenuating the mean orofacial ratings by 21.8 ± 7.3%.Conclusion: Of all orodental factors considered, only edentulism and complete denture wearing influenced oral TD expression, calling for the close monitoring of the dental status in antipsychotic drug-exposed patients to prevent tooth loss. Further studies to measure the impact of an adequate prosthodontic rehabilitation in edentulous subjects with orofacial TD seem warranted.

Mental health and disaster related attitudes among Japanese after the 2011 Fukushima nuclear disaster

2012-02-20

On March 11, 2011 Japan was struck by a magnitude 9.0 Mw earthquake. The results were severe with more than 15,000 people being killed by the earthquake and the following tsunami (). The aftermath of the disaster was a level 7 nuclear meltdown at Fukushima, matching only the Chernobyl disaster (). The literature of behavioural reactions after nuclear disasters is scarce (; ; ), mainly addressing anxiety. Moreover, in the case of Japan, the nuclear disaster has awakened the memories of the WWII atomic bombs and as such, might have raised historically-based panic among the Japanese (). Due to intergenerational transmission of past trauma, the grandchildren of those who survived the dropping of the atom bombs on Hiroshima and Nagasaki may be at high risk of developing mental distress following the current disaster. Parental distress is presumed to be transferred to offspring through maladaptive, postnatal maternal behaviours (), child-rearing behaviours (; ), and parental communication of the trauma (). Intergenerational transmission of traumatic experiences was found to escalate when second (; ) and third () generation Holocaust survivors were confronted with adverse life events. It is assumed that memories of WWII and the dropping of the A-bombs will be awakened due to the nuclear disaster caused by the Sendai earthquake. These memories will affect the grandchildren of the A-bomb survivors more intensely.

The negative effects of MST and combat injuries among female soldiers: A major concern

Nancy Lutwak — 2012-03-14

The recent publication, Gender differences in traumatic experiences and mental health in active duty soldiers redeployed from Iraq and Afghanistan, Maguen S, Luxton, DD, Skopp NA, Madden E, focuses on several important findings. It highlights that PTSD symptoms may be increased among female veterans who have been injured in combat. The authors also discuss that significant mental health sequelae result from combat injuries in women.

Concerns about data reporting and interpretation in “Efficacy and tolerability of the novel triple reuptake inhibitor amitifadine in the treatment of patients with major depressive disorder: A randomized, double-blind, placebo-controlled trial”

David M. Marks, Jonathan S. Abramowitz, Glen I. Spielmans — 2012-05-01

reported results from a proof-of-concept placebo-controlled study of amitifadine in major depressive disorder and made comparisons to other antidepressant drugs with respect to drug-placebo differences and effect size. We have concerns about how data were reported as well as the validity of these comparisons. Specifically, Tran et al.’s primary outcome measure was “the change in the total score on the Montgomery Asberg Depression Rating Scale (MADRS) from baseline to the end of treatment” (Section 2.3, “Outcome Measures”), and they assert that “the difference between amitifadine and placebo for mean change from baseline in MADRS score was 3.8” (Section 4, “Discussion”). However, according to Table 3, 3.8 is actually the group difference in adjusted mean MADRS scores at end of treatment (Week 6) as opposed to the difference in mean change from baseline. In actuality, the mean change from baseline to endpoint in the groups are as follows, using the baseline MADRS scores from Table 2 and the posttest scores from Table 3: amitifadine (30.6–18.2) = 12.4; placebo (32.2–22.0) = 10.2. These results indicate that the difference between amitifadine and placebo for mean change from baseline in MADRS score was only 2.2. Indeed, placebo accounted for 82% of the effect of amitifadine.

Response to Marks, Abramowitz, and Spielmans Letter to the Editor

2012-05-01

To the Editor: We appreciate Drs. Marks, Abramowitz, and Spielmans careful review and comments on the details of the statistical analysis and the discussions on the findings in relation to the overall efficacy of antidepressants in general of our manuscript entitled “Efficacy and tolerability of the novel triple reuptake inhibitor amitifadine in the treatment of patients with major depressive disorder: A randomized, double-blind, placebo-controlled trial.”