Do antipsychotic augmentation work in SSRI resistant OCD? Int Jl Neuro Psy.April.2013

25.04.2013

SSRIs are the drugs of first choice in OCD.Soomro et al’s 2008 Cochrane review did not find any difference in efficacy between different SSRIs.Half of OCD patients do not respond to initial SSRI trial.Change to another SSRI is the recommended strategy.Tricyclics and antipsychotic augmentation strategies are third line of treatment.Antipsychotics are suggested based on hyper dopaminergic state in OCD.

Markus Dold, Martin Aigner, Rupert Lanzenberger and Siegfried Kasper  from Vienna report the results of the metaanalysis of all double blind placebo controlled RCTs in which adult OCD patients received SSRI plus antipsychotics compared against SSRI plus placebo.Primary outcome measures were 1.Change in mean YBCOS score 2. the  response rate. Decrease in YBOCS score of 35% or more was defined as response.

From the initially identified 1494 abstracts, 12 studies were identified that meet all inclusion criteria having a total of 294 patients.Five studies examined  augmentation with Quetiapine , three with Risperidone , two with Olanzapine  and one each with Aripiprazole  and Haloperidol each.

Results

28% of patients in augmentation group reached response criteria compared with 13% in placebo group. Pooled relative risk was 2.10 ( ie significant effect) and NNT was 6.

Subgroup analysis showed that only Risperidone had significantly higher effect size than placebo when both response rate ( dichotomous data) and changes in YBCOS total score (continuous )were both considered.Other antipsychotics did not show more efficacy than placebo on response rates. Total score changes showed Aripiprazole and  Haloperidol also as effective.

Only risperidone showed significant efficacy in both the outcome measures.( ie relative risk based on response rates and standardised mean difference based on total score changes). Though Aripiprazole and Haloperidol were effective in total score changes , this was based on only one trial.

Conclusions: This analysis suggest Risperidone as the preferred agent for augmentation of SSRI in OCD.

Limitations: Small number of participants.Large variation between studies in terms of participant inclusion criteria.

Haloperidol and Risperidone are more potent D2 blockers than other antipsychotics tested.D2 receptor involvement is likely in OCD.

Numbers:

Relative Risk: Numerical values >1 indicate a larger response to antipsychotic augmentation than to placebo medication. If the reported 95% CI do not include the value of 1, a statistically significant effect can be assumed.

Continuous data (YBOCS changes) were analysed using standardized mean differences (SMDs) with the associated 95% CI. Numerical values >0 indicate a positive (beneficial) effect of the adjunctive antipsychotic.

Summary of the article:

Antipsychotic augmentation of serotonin reuptake inhibitors in treatment-resistant obsessive-compulsive disorder: a meta-analysis of double-blind, randomized, placebo-controlled trials. Dold M, Aigner M, Lanzenberger R, Kasper S. Int J Neuropsychopharmacol. 2013 Apr;16(3):557-74

Do vaccination against nicotine work? Am Jl Psy.April.2013

25.04.2013

Smoking continue to be one of the biggest public health problems. Nicotine work via nicotinic receptors in brain.B2 subunit of this receptor is considered crucial to nicotine’s effects. If we can induce the body to produce anti nicotine antibody that binds to nicotine that  would then reduce the amount of nicotine reaching brain. ( the nicotine-antibody complex is too large to cross blood brain barrier). That would mean that less activation of reward centres and thus less craving. Would such a vaccine work as we think?

Esterlis et al.reports the results of a proof of concept study based on the above assumption.The vaccine was 3:aminomethylnicotine conjugated to recombinant Pseudomonas exoprotein A (3:-AmNic-rEPA).This has high affinity for nicotine.

Study: Four to five injections of 400 mg each of this vaccine was given to eleven non-treatment-seeking tobacco smokers. They  were scanned  (SPECT or receptor binding) before and after four monthly immunisations.Subjects  abstained from tobacco  for the 5 days before each SPECT scan day to allow for any nicotine or metabolites to clear the brain. ( as they may compete with radiotracer binding).  To check whether immunisation has the desired effect, subjects were given IV nicotine and scans were repeated  to measure binding to receptors.

 Findings:

There was a significant increase in antibody concentrations over the course of the treatment. A maximal binding of 55% of the b2 subunit was observed before vaccination, which was reduced by 11%   after vaccination.  Immunization results in 30%–90% less nicotine entering the brain after acute nic- otine exposure. Administration of iv nicotine after immunization was associated with plasma nicotine concentrations at least twice as high as before immunization. Subjects reported 40% reduction in cigarette use and a significant reduction in craving for cigarettes from baseline to completion of immunization.

Limitations:The lack of a placebo control group limits clinical interpretation.Study has only 11 participants.

Comments: 11% decrease in binding seems small and unlikely to affect the reward experienced from smoking enough to result in clinical effects.In the accompanying editorial Fagerstrom and Tonstad comment that smoking is not just about nicotine. However, the concept of vaccines against nicotine is quite interesting though the clinical results so far has not been convincing.

Summary of the article:

Effect of a Nicotine Vaccine on Nicotine Binding to β2*-Nicotinic Acetylcholine Receptors In Vivo in Human Tobacco Smokers.

Esterlis I, Hannestad JO, Perkins E, Bois F, D’Souza DC, Tyndale RF, Seibyl JP, Hatsukami DM, Cosgrove KP, O’Malley SS. Am J Psychiatry. 2013 Apr 1;170(4):399-407.

Do mothers depressive cognitions predict offspring’s cognitive style in adulthood? Am.Jl.Psy.April.2013

 24.04.2013

Preventing depression is an enormous  public health challenge.Negative life events are known to trigger depression.We may not be able to prevent negative events in life, but preventing  the depressogenic interpretation of events is possible. Depressogenic interpretations include the tendency to attribute negative events to causes that are internal ( I caused it), stable (it will not change) and global (everything is like this).

How do we develop depressogenic cognitive style? Genetic factors play a small role. Experiences play a crucial role. Explanations provided by mother/other significant figures might be important in shaping one’s cognitive style. Studies have suggested that negative and critical maternal feedback is associated with depressogenic  cognitive styles in children.If there is  such an  association between cognitive styles of mother and child,  is it mediated through maternal depression? ( ie cognitive style of mother might be linked to maternal depression and this could increase the risk of depression in offspring)

Rebecca M. Pearson,  Charles Fernyhough,  Richard Bentall, Jonathan Evans, Jon Heron,Carol Joinson, Alan L. Stein and  Glyn Lewis from UK investigated the nature of association between maternal cognitive style measured during pregnancy and offspring cognitive style 18 years later and explored how any such association was related to  maternal depression.Data from 2528 mothers ( cognitive  style and depression) and children (cognitive style and depression at age 18) was analysed.

Findings:

A positive association between maternal and offspring cognitive style was observed. Maternal depression  did increase the offspring depressogenic cognitive style score. When maternal cognitive style was taken in to account this increase was much less only. An increase of approximately one standard deviation in maternal cognitive style score was associated with an increase of approximately 0.1 standard deviations in offspring cognitive style score at age 18.Maternal and offspring cognitive styles explained 21% of the association between maternal and offspring depression.

Is this association due to link between maternal and offspring depression? Association remained after adjustments for maternal and offspring depression, indicating that this alone do not explain the association,it might be that maternal and child cognitive styles mediate a significant part of the association between maternal and offspring depression.

Strength of the study: large sample size with the long-term follow-up spanning the life of offspring from before birth into adulthood. information about  confounding variables available ( eg concurrent measures of both maternal and offspring depression).

Limitations: Measurement of maternal and offspring cognitive style differed. Lack of a parenting measure limits our understanding as to how maternal cognitive style influenced the offspring.

Conclusions: Cognitive styles appear to be transmitted to offsprings. This might be one potential pathway linking maternal to offspring depression that is modifiable/preventable.Maternal cognitive style could be modified using CBT approaches. It can be treated with medications if part of depression. These will help in preventing transmission by observation/imitation/absorption  of cognitive styles.

This is the first study to provide evidence for an influence, persisting into early adulthood, of a mother’s cognitive style on her offspring’s cognitive style.

Summary of the article:

Association between maternal depressogenic cognitive style during pregnancy and offspring cognitive style 18 years later.

Pearson RM, Fernyhough C, Bentall R, Evans J, Heron J, Joinson C, Stein AL, Lewis G.Am J Psychiatry. 2013 Apr 1;170(4):434-41

Do resting state brain activity differ in Schizophrenia and Depression? Schiz Bulle.March.2013

23.04.2013

During goal directed activity (away from oneself), some brain regions show decreased activity. Activity in these areas spring back  while at rest or engage in self referential tasks. This brain network is the default mode network and includes superior and inferior anterior medial frontal regions, lower precuneus, and posterior lateral parietal cortices. This network plays a crucial role in self-referential processing.

Self referential tasks (tasks that involve perspective taking of intentions, beliefs and desires of others, remembering own past,planning own future ) are altered in schizophrenia and depression.  Self- outside boundaries are blurred in schizophrenia ie  fails to differentiate exogenous from endogenous stimuli. self referential (self generated)  memory is poor in schizophrenia but external source memory is intact. Medial frontal cortex is the key to self referential processing. As self referential processing is poor, hypoactivity in medial frontal cortex is expected in schizophrenia. Self focus is increased in major depression ie negative ideas are extensively attributed to self and  this manifest in rumination. As self referential processing is increased, the resting state  is likely to be hyperactive in depression.

Contrasting resting state function is expected in these two disorders. Is this supported by evidence?

Simone Kuhn and Jurgen Gallinat report the results of a meta analysis of all  f MRI /PET studies on resting state alterations in medial frontal cortex that compared patients with healthy controls. Meta-analysis include 11 studies reporting 140 foci of altogether 567 participants for schizophrenia and 11, studies with 70 foci of altogether 470 participants for depression.

Results

There is a decrease in resting-state (hypoactivity) compared with healthy controls in ventromedial prefrontal cortex (vmPFC) in schizophrenia. In contrast, hyperactivity was seen in major depression.

Conclusions

Resting state activity is reduced in schizophrenia. This could explain the reduction in self referential processing and  lack of insight. In contrast to this, resting activity is increased in depression and this goes with the idea of increased  rumination and self focus in depression.

Summary of the article:

Resting-state brain activity in schizophrenia and major depression: a quantitative meta-analysis.

Kühn S, Gallinat J.Schizophr Bull. 2013 Mar;39(2):358-65

Is stress associated with cognitive decline? Psych Med.March.2013

22.04.2013

Cognitive function/ decline is influenced by age, educational attainment and genetic factors like APOE. Stress might also have a role to play in these changes. Activation of HPA axis and subsequent increase in glucocorticoids may  initiate changes in hippocampus and other areas . Social stress  ( a broad term encompassing both external emotion-provoking stressors (stressful life events) and internal responses (perception and adaptation) to a given stimulus) is shown to have both positive and negative effects on cognition.Ongoing high-stress level may impair working memory where as moderate/ acute stress can enhance some cognitive functions. For example: Rosnick et al showed that individuals who had experienced the injury or illness of a friend performed better in episodic memory, attention and psychomotor speed tasks. A Swedish study in an older population (Grimby & Berg, 1995) revealed that cognitive decline occurred regardless of stressful life experiences. Literature is inconclusive on the effects of stress.Differences in study design ( cross sectional may not be best suited), stress measures  (events or perceived  stress) and support available etc might be contributing to this inconsistency.

Y. Leng and colleagues from UK (Cambridge and Newcastle Universities) studied both objective and subjective measures of social stress and cognitive function in a middle- to older-aged English sample ( 5129 participants ) using data from the European Prospective Investigation of Cancer (EPIC)-Norfolk prospective cohort study.

Cohort: In the 5 yrs preceding assessment, half of the participants reported no life events. 18% had atleast one longterm difficulty in that period. Those who have achieved lower educational levels reported significantly higher stress levels and more long-term difficulties. Participants with low MMSE scores were older, more likely to be women and to have come from a lower social class, and to have achieved a lower educational leve

Findings:

Those who reported slower adaptation to life events were more likely to have lower cognitive function, but the association was attenuated when adjusted for physical health conditions.Higher perceived stress was associated with lower cognitive function and this remained significant after adjustment for all factors.This association was particularly noted among less educated. These differences in cognitive function seemed to be restricted to individuals who reported extreme levels of stress. None of the objective measures of stress in this study were associated with cognitive function.

Limitations: The assessment of psychosocial factors preceded the cognitive assessments by a median of 10.5 years. Base line cognitive functions were not measured and hence  the question whether stress is a risk factor for poor cognition or is it an early marker cannot be answered. MMSE has limitations  ( eg lack of sensitivity for detecting mild cognitive impairment ).

Conclusions: This is the largest study on the association between stress and cognitive function and the  findings are consistent with observational epidemiological studies, where self-perceived stress was found to be associated with cognitive impairment.

Summary of the article:

The association between social stress and global cognitive function in a population-based study: the European ProspectiveInvestigation into Cancer (EPIC)-Norfolk study.Leng Y, Wainwright NW, Hayat S, Stephan BC, Matthews FE, Luben R, Surtees PG, Khaw KT, Brayne C.

Psychol Med. 2013 Mar;43(3):655-66.

Is combining direct electrical stimulation with antidepressants more effective in depression? :JAMA Psy.April.2013

19.04.2013

Recent times have witnessed a surge in research on Transcranial Direct Current Stimulation (tDCS). Trials in 1960s produced mixed results and though approved  for clinical use in many countries, (USA Israel, Canada, and Brazil etc),it has not been widely adopted in clinical settings.

The treatment involves application of weak, direct electrical current to the brain through  large electrodes  placed over the scalp. Anodal and cathodal stimulation increases and decreases cortical excitability, respectively.It is thought that this will induce significant long- lasting neuroplastic effects.Left dorsolateral prefrontal cortex (DLPFC) is hypoactive in depression and, anodal tDCS would  increase activity in this area and thus restore prefrontal activity. Recent studies show  mixed clinical results. Evidence for neurogenesis is emerging. A recent meta-analysis suggested that the technique might be effective for depression, but further trials are necessary for firm conclusions.

Andre R. Brunoni and colleagues from Brasil report the results of large RCT  with 120 participants having non psychotic depression. tDCS plus sertraline was compared against either alone.Participants were randomized to 4 groups: sham tDCS and placebo ( placebo), sham tDCS and sertraline (sertraline only), active tDCS and placebo (tDCS only), and active tDCS and sertraline (combined treatment).

Intervention entailed a short-term treatment period in which ten  30- minute  tDCS sessions were given to subjects in the first two weeks followed by single stimulation sessions on week 4 and week 6 . Patients  thus received total of 12 sessions. Study was continued as open label after this RCT phase.Stimulation (Brifrontal) was done with electrodes placed on areas corresponding to left and right DLPFC using a direct current of 2 mA for 30 min/d for 10 days, followed by 2 extra tDCS sessions every other week until the study end point (total charge density of 1728 coulombs/m2).Pharmacological intervention was a fixed dose of sertraline  50 mg/d.The primary efficacy outcome was the Montgomery-Asberg Depression Rating Scale (MADRS) score at 6 weeks.

Results

Combined treatment differed significantly from placebo (mean difference, 11.5 points; 95% CI, 6.03 to 17.10; P=.001), tDCS only (mean difference, 5.9 points; 95% CI, 0.36 to 11.43; P = .03), and Sertraline only (mean difference, 8.5 points; 95% CI, 2.96 to 14.03; P=.002).No difference was observed between tDCS only and sertraline only. Greater response seen in patients with melancholic depression.resistant cases showed less response. greater baseline severity showed greater response to the combined treatment. Benzodiazepine use, even in low dosages, induced lower effects in the tDCS-only group.

 Conclusions: Combined treatment is more effective.tDCS is comparable to antidepressant. The efficacy of tDCS appeared to be greater compared with recent rTMS trials. tDCS is not associated with hazardous cognitive effects.

Limitations: Dose of Sertraline used is very low. The intervention require 20- to 30-minute daily sessions for several weeks (practical limitations). There were 7 episodes of treatment-emergent mania or hypomania, 5 of which occurred in the combined treatment group.

StatiBit:

Confidence Interval:  CI  shows how “good” an estimate is ie how sure we are that the estimate of effect  will fall in the given range. In this study, we are 95% confident that the combined treatment will reduce the depression symptom score by a measure between 6.03 and 17.10 points. ie  if we repeated the trial for similar samples  (taken from the general population of patients with depression), then 95% of the estimates arising from those trials will be with in this range.

 Summary of the article:

 The Sertraline vs Electrical Current Therapy for Treating Depression Clinical Study: Results From a Factorial, Randomized, Controlled Trial.

Brunoni AR, Valiengo L, Baccaro A, Zanão TA, de Oliveira JF, Goulart A, Boggio PS, Lotufo PA, Benseñor IM, Fregni F.JAMA Psychiatry. 2013 Apr 1;70(4):383-91.