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.
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.
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
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.
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:
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.
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.
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:
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
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.
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.
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:
Kühn S, Gallinat J.Schizophr Bull. 2013 Mar;39(2):358-65
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
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.
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.
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.
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:
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.
Psychotic disorders are marked by lack of insight/ poor insight in to the illness.Poor insight negatively affects adjustment, recovery,engagement and relationships. Insight ( the awareness of having a mental disorder and being able to recognise the symptoms and the need for treatment or help from others) , though extremely important in the recovery process, is seldom addressed as primary outcome measure in research. Symptom improvement do not necessarily mean regain of insight.It could be a domain that is relatively independent of symptom improvement. Previous review on change in insight during treatments by Henry and Ghaemi (2004) highlighted lack of studies in this area. Has the scene changed since then? Pijnenborg GH, van Donkersgoed RJ, David AS and Aleman A (Netherland and UK) report the results of a met analysis on this question.
The authors included only randomised controlled trials in patients with schizophrenia or another psychotic disorder where insight was assessed with a validated measure. Search yielded 350 abstracts, 30 met the initial inclusion criteria. 19 studies were selected in the treatment effect analysis.
The mean weighted effect size of all studies on treatment-effects insight in psychosis together is 0.34 (95% CI = 0.12–0.57) . This is a medium effect size. No publication bias was observed. Heterogeneity ( ie studies report a wide range of results ) of intervention effect was observed.
Interventions studied include CBT,Psycho-education,Adherence therapy ,Social skills training ,Video self-observation and Comprehensive Interventions.Three of these encompassed at least 3 studies (CBT, psycho-education and adherence therapy). The ES for CBT was small, there was no significant effect for psycho-education (may be due to a lack of power i.e. due to very small sample size ) and adherence therapy did not have an effect.There was only one medication(McEvoy et al., 2006) study and effect size after twelve weeks was small.
Two studies that examined comprehensive interventions (combination of psycho-education, skills training and CBT) showed a large ES and are thus considered promising.
A few studies have looked at the effect of clozapine on insight. These studies did not use a randomized controlled design and was not included in this analysis.
Limitations: few studies,small sample sizes.
Conclusions: Available evidence supports the possibility of improving insight with interventions.
Statistical bit: Effect size is used to quantify the difference between two groups ( control vs experimental) .ie how much is the size of the difference?. It is the standardised mean difference between the two groups. An Effect size of .3 would mean that 62% of control group participants would be below the average person in experimental group.
Summary of the article
Pijnenborg GH, van Donkersgoed RJ, David AS, Aleman A.Schizophr Res. 2013 Mar;144(1-3):109-17
Glutamatergic system is intensely researched for potential psychotropic medications. Glutamate (Glu) is the major excitatory neurotransmitter in the brain, Glu neurons project within the cortex and to subcortical regions, such as locus coeruleus, raphe nucleus, and substantia nigra, where they modulate monoaminergic systems.NMDAR is one of the specific types of receptors for glutamate.The overstimulation of NMDA receptors leads to neurodegeneration through a process called excitotoxicity. Antagonism of NMDAR may represent an effective anti- depressant mechanism. Many antidepressants are shown to induce alteration in NMDAR functioning. Acute i.v. administration of the NMDAR non-competitive antagonist Ketamine, results in rapid symptom alleviation in patients with depression and suicide ideation.However, direct NMDAR antagonism may also change dopamine levels leading to psychotic states. Another way to influence NMDAR is via Glycine site on the receptor .
The question is this. Would an antagonist at Glycine site alleviate depression with out the risk of psychotomimetic effects of direct NMDAR antagonism?
Uriel Heresco-Levy, Genia Gelfin, Boaz Bloch, Raz Levin, Shani Edelman, Daniel C. Javitt and Ilana Kremer attempted to answer this question. They used D cycloserine (DCS) (an antibiotic used to treat Tuberculosis) ,a partial agonist at the NMDAR glycine site, with agonist effects predominating at low dose and antagonist effects predominating at high dose.DCS has been assessed in treatment-resistant schizophrenia. At low doses, DCS produced beneficial effects in some studies ; at higher doses it was found to exacerbate psychosis. A previous trial of low dose of DCS was not effective in depression and it appears that higher dose (ie above 500 mg) is required for the antagonistic activity.
26 adult out-patients with Recurrent Major Depressive Disorder, currently resistant to treatment (defined as 20 plus score on the 21-item Hamilton Depression Rating Scale, despite two or more adequate antidepressant medication trials) and been treated for at least 4 wk with a stable clinically determined dose of antidepressant medication, were randomised using a double-blind, placebo controlled parallel group design to receive increasing dose of DCS or placebo.The mean duration of the current episode was 13-14 months.
DCS treatment led to significant improvement in depressive symptoms as measured by HAMD.Seven of 13 (54%) patients assigned to DCS qualified as responders (i.e. 50% HAMD total score reduction) vs. two of 13 (15%) assigned to placebo. Five of 13 (38 %) patients assigned to DCS were also considered remitters (i.e. HAMD total score below 7) vs. two of 13 (15%) assigned to placebo, although this difference was not statistically significant. More patients ( 3 against one in placebo group) withdrew from experimental arm siting discomfort as reason.
Limitations: Small study. Remission rates were not statistically significant.
Conclusion: This study provides proof of concept evidence that antagonistic activity at the NMDAR-associated glycine site can induce antidepressant effects and reduce MDD severity. 54 % of DCS-treated subjects achieved treatment response. This is to be considered against the usually reported 60-65% response rate to the first antidepressant agent in depression. Authors also measured serum glycine levels and comment that treatment targeting NMDAR glycine site may be particularly appropriate in those with high glycine levels.
Summary of the article:
Heresco-Levy U, Gelfin G, Bloch B, Levin R, Edelman S, Javitt DC, Kremer I. Int J Neuropsychopharmacol. 2013 Apr;16(3):501-6.
Mother-infant attachment/interaction is conceptualised as an emotional bond that influence the behaviour “from the cradle to the grave” ( Bowlby,1969).Interactions with peers early in life is also considered important in shaping future relationships.Most animal studies have focused on the role of maternal care.
Igor Branchi , James P. Curley ,D’Andrea I, Cirulli F, Champagne FA and Alleva E ( Italy & USA) report the results of a novel study that addressed the relative contributions of maternal and peer relatiosnhips.They used the communal nest paradigm in which three lactating females ( mice) place their litters ( each with 3 days differing in age) together in a single nest and engage in shared care-giving from birth to weaning. The standard condition was one dam rearing her own litter. Maternal behaviour and pup social interactions were monitored. When they reached adulthood, social behaviour was assessed using a social interaction test where in a neutral venue, after two weeks of isolation, each was exposed to a standard opponent and behaviour ( aggression, subordination, affiliation,nonsocial etc) was recorded. Brain BDNF and Oxytocin receptor levels were also measured in adulthood.
Early interactions with mother and peers independently shape social skills, brain BDNF expression and Oxytocin receptor binding in the amygdala at adulthood.High levels of interactions with mother and peers predicted elaborate social competencies and with elevated brain BDNF levels.
High levels of peer interactions in the nest were selectively associated with high adult affiliative behaviour (the display of behavioral patterns aimed at reducing aggressive behavior and increasing social tolerance) and increased OTR binding in different nuclei of the amygdala.Enhanced affiliative behavior emerged only in those groups who displayed high levels of early peer interactions during infancy — and independently from the amount of maternal care — suggesting that different adult social domains are structured through diverse early social experience.
Those having received a combination of both high levels of maternal care and peer interactions during infancy displayed rapid social learning and social plasticity.The groups exposed to high levels of both social components showed significantly higher hippocampal, frontal cortical and hypothalamic BDNF protein levels compared to the other two groups, which were exposed to high levels of only one component.
Both components are critical for the development of the adult social agonistic competencies (the ability to manage social interactions, playing either the dominant or the subordinate role ).
These findings would help future studies aiming to investigate the neurobiological mechanisms underlying how pathological aggressive behavior can lead to an escalation of violence without inhibitory control associated to affiliative behavior and reconciliation.
The study highlights the importance of early life relationships. Impoverished early relationships can lead to dysfunctional neurobiological systems .This can set the ground for maladaptive behavior and disability.
Another interesting observation was that the amount of maternal care received changed according to birth order, with the Middle group receiving the least amount of care. This might be probably the case in humans as well.
Summary of the article:
Branchi I, Curley JP, D’Andrea I, Cirulli F, Champagne FA, Alleva E.Psychoneuroendocrinology. 2013 Apr;38(4):522-32.