Is Nalmefene ( as needed) safe and effective in reducing heavy drinking? Jl psychopharm.Aug. 2014


Alcohol dependence is a major public health problem. Even in countries where free healthcare is available universally, proportion that receive treatment is miniscule. Abstinence oriented treatment may not be acceptable to many. Treatments that aim at reducing drinking have a special place in dealing with this problem.

Nalmefene is an opioid modulator . It is licensed to treat dependent individuals with continued high drinking risk. Previous studies ( lasting up to 6 months) have shown that it is well tolerated and safe . SENSE study group ( Amsterdam University) who carried out those studies report the long term efficacy , tolerability and safety of Nalmefene in this report.

This RCT recruited 675 alcohol dependent patients ( from 60 sites across europe). Those with ALT/AST more than 3 times normal were excluded. Patients in withdrawal or those with less than 6 heavy drinking days in last month or abstinent for 14 days in last month were excluded.Patients with a stable comorbid psychiatric disorder were eligible for inclusion.Patients were followed up for 52 weeks.

Patients took the medicine on an AS NEEDED Basis  ( i.e. if they thought they might drink, 1-2 hrs prior to the anticipated drinking)  up to once daily.


Two randomised groups were similar to start with. Majority met medium drinking level  with   (on average ) 1 4 heavy drinking days in last month. Majority were not treated for dependence or withdrawal previously. 32% of placebo treated and 38% of Nalmefene treated patients dropped out during the study.

Change in heavy drinking days were not statistically significant at 6 months.

At month 13 Nalmefene was more effective  both in the reduction of heavy drinking days (group difference: − 1.6 days/month [95% CI – 2.9; − 0.3]; p = 0.017) and total alcohol consumption (group difference: − 6.5 g/day last month [95% CI – 12.5; − 0.4]; p = 0.036).

Almost 40% of the patients in the full-analysis set substantially decreased their alcohol consumption already in the period between screening and randomisation, i.e. prior to taking any study medication. Once these subjects were excluded , the rest of the participants ( i.e. Target efficacy population: 33% of  full group) showed an effect of Nalmefene compared to placebo, both for the number of heavy drinking days  and total alcohol consumption.effect is more on total alcohol consumption.

63% of placebo group and 75% of Nalmefene group had adverse effects.These were transient and mild/moderate in intensity. 5% of placebo group and 11% of Nalmefene group dropped out due to  side effects. Nausea, insomnia and loss of appetite were the common side effects. Disorientation episode was reported in two Nalmefene treated patients.

 62% of the nalmefene-treated patients in the total population completed the 1-year study which is quite good in this condition.

Limitations: levels of psychiatric comorbidity were lower as compared to usual subjects with this condition treated in psychiatric settings. The fact that 40% of participants significantly reduced their drinking between randomisation and study initiation is worth noting.

Nalmefene is an effective treatment for alcohol-dependent patients who continue to have high/very high risk drinking levels 1–2 weeks after an assessment of their alcohol use.

Comments: The significant reduction in alcohol use before the start of study medication points towards the efficacy of brief interventions.

Summary of the article:

Long-term efficacytolerability and safety of nalmefene as-needed in patients with alcohol dependence: A 1-yearrandomisedcontrolled study.

van den Brink W, Sørensen P, Torup L, Mann K, Gual A; for the SENSE Study Group.

J Psychopharmacol. Aug, 2014. 733-744.

Is abnormal maternal CRP levels indicative of offspring risk for schizophrenia? Am Jl Psy. Sept.2014

Prenatal infection and immune activation is one line of enquiry in schizophrenia research.Associations have been reported with maternal antibody to influenza, rubella, toxoplasma gondii, and herpes simplex virus type 2. animal research supports the idea that such activations can have impact on brain. Would maternal C Reactive protein be associated with schizophrenia in offsprings?

Sarah Canetta and team of researchers  from New York and Finland used data from  Finnish Prenatal Study of Schizophrenia to explore this link. Both Finnish national birth cohort and the national case registry are comprehensive in its coverage. All offspring born in Finland from 1983- 1998 were included.


There was a significant association between increasing maternal C-reactive protein and risk of schizophrenia (odds ratio=1.12, 95% confidence interval =1.02–1.24, p=0.02. Magnitude of this association increased when adjusted for covariates like maternal age. Every 1 mg/L increase in maternal C-reactive protein, the risk of schizophrenia was increased by 28%. If mother’s CRP level was abnormal (i.e.  above 10 mg/l)  the risk increased by odds ratio of 1.58 ( 95% CI=1.04–2.40, p=0.03).But when this was adjusted for various covariates, the difference didn’t reach statistical significance.

This sample had relatively younger ( mean age 23) subjects and  it is possible that the observed  association is relevant only for early onset schizophrenia.It is also possible that CRP elevation is related to an earlier onset of the disease in persons at risk for other reasons.

Similar results were reported with autism previously , so the risk may not be specific to schizophrenia. It is possible that immune activation primes brain and the interactions with genetic and environmental factors in certain developmental windows might be deciding the outcomes.

Conclusion: Elevated maternal  CRP is associated with an increased risk go schizophrenia in offsprings.

Comments: Would reducing infections / inflammations during pregnancy  help in reducing incidence of schizophrenia?

Summary of the article: 

Elevated maternal C-reactive protein and increased risk of schizophrenia in a national birth cohort.

Canetta S, Sourander A, Surcel HM, Hinkka-Yli-Salomäki S, Leiviskä J, Kellendonk C, McKeague IW, Brown AS.

Am J Psychiatry. 2014 Sep 1;171(9):960-8

How do some older individuals with Amyloid Plaques maintain normal cognition? Nature Neuroscience.Sept14.2014


Accumulation of Amyloid B peptide is considered as an early event in Alzheimer’s disease.(AD). It is intriguing that some older people with extensive deposits of these peptides do not go on to have AD. fMRI studies show that they may have increased neural activity during cognitive activity than young people or older people without plaques. Is this increased activity beneficial ?

Jeremy A Elman and team of researchers at University of California adopted an f MRI task to look at the relationship between fMRI activation and amount of memory detail for an encoded stimulus.

22 healthy young adults and 59 older people with normal cognition participated in this study. 33 of the older adults had no brain A Beta peptide and 16 had these deposits. Subjects then studied pictures of scenes (under fMRI) and after 15 minutes they were tested for ‘gist memory’ ( i.e. the central meaning of the scene). They viewed written descriptions of scenes and had to state whether these descriptions matched the scenes previously seen. Memory richness was tested by asking true false questions about the scenes.Brain activations during encoding for items subsequently remembered during the gist task (hits) were assessed.

Results: Young people showed greater increases in activity with more details remembered within task-positive areas. Old individuals without plaques demonstrated relatively little modulation in task-positive regions, they showed greater deactivation with more recalled details in the task-negative network, as compared to young subjects. Old subjects with plaques showed stronger parametric effects than those without in parietal and occipital cortex, particularly in the right hemisphere. They showed reduced deactivation in task-negative regions, but increased activation in task-positive regions related to more detailed memory encoding.  

Conclusion: Authors conclude that increased neural activity in those with brain Aβ is a beneficial process that reflects neural plasticity and is a compensatory function. It is also thought that these compensatory mechanisms could eventually fail.

Comments: If we could further understand how these compensatory mechanisms work, opportunities may arise to prolong or augment them.

Summary of the article:

Neural compensation in older people with brain amyloid-β deposition.

Elman JA, Oh H, Madison CM, Baker SL, Vogel JW, Marks SM, Crowley S, O’Neil JP, Jagust WJ.

Nat Neurosci. 2014 Sep 14. doi: 10.1038/nn.3806. [Epub ahead of print]

Is there enough evidence to classify schizophrenia in to type A and Type B ? Brit Jl Psych.July.2014


Classifications and ‘declassifications’ are not new to schizophrenia. DSm 4 had 5 subtypes, DSm5 removed them all. Icd 10 still has 8 subtypes. Symptom dimensions ( positive, negative , affective and cognitive ) are accepted  as the more useful way to subtype this disorder in the new classifications.These classifications do no reflect the clinically valid concept of treatment responsive and treatment refractory schizophrenia. Oliver Howes and Shijit Kapur argue that the biology behind treatment response should be  one guiding factor in classification.

Evidence for pre synaptic dopamine dysfunction  in schizophrenia is robust. Over 50 in vivo molecular imaging studies support this. Demonstration of substantial D2 blocking by effective antipsychotics provide converging evidence in support of dopamine theory.

Why do not all patients on Dopamine blockers improve? PET imaging  show that some patients show little or no response even with high levels of dopamine receptor blockade.

Are there any difference in dopamine system between responders and non responders?

Dopamine metabolite level studies show a bimodal distribution i.e. there is a group with high dopamine and another one with no alteration. Patients who responded show higher dopamine levels in striata in postmortem studies compared with those who did not respond.  Amphetamine do not increase psychosis in a subgroup of schizophrenia.  Dopamine synthesis capacity was increased in treatment responsive group compared to resistant group.

Based on the above observations, authors argue that may be there are two biological types of schizophrenia: the A- hyper dopaminergic, type B- norm dopaminergic. There are potential advantages to such attempts, as focusing on mechanisms will help open some doors to new treatments. Early identification of Type B patients would perhaps help them to choose clozapine early on.  PET imaging of dopamine may help make such decisions.

What underlies type B?  probably glutamatergic mechanisms. we don’t know now. Authors are of the view that it is time to move on from descriptive typing.

Summary of the article:

neurobiological hypothesis for the classification of schizophreniatype A (hyperdopaminergic) and type B(normodopaminergic).

Howes OD, Kapur S. Br J Psychiatry. 2014 Jul;205(1):1-3.

What makes us happy? insights in to subjective well being: PNAS.Aug.2014.


Happiness is a difficult concept to define and measure. One foundation on which concept of happiness  is built is rewards. Momentary measures of happiness ( =hedonic well-being) can be  studied by sampling the experiences of individuals and analysing how these are related to antecedent life events /rewards. However, we do not know much about how the cumulative influence of such  daily life events are aggregated into subjective feelings.

Is it the outcome of tasks ( reward) or the expectation that determine happiness?

What are the brain correlates of such momentary happiness?

Can the happiness be predicted using computational models / formula?

Robb B. Rutledgea, Nikolina Skandalia, Peter Dayanc, and Raymond J. Dolan from  University College London reports the results of an interesting study that attempts to answer these questions?

Participants performed a probabilistic reward task (gambling) and were asked about their level of happiness after every few trials. ( i.e. overall emotions state ). Participants were scanned   (fmRI) while they made choices. The team created a computational model of momentary well-being that includes expected values of chosen gambles and the difference between experienced and predicted rewards ( both from dopamine activity) and looked at its ability to predict momentary happiness. Additional behavioural experiments were carried out to validate these models. 18420 people participated in a smart phone experiment ( The great brain experiment/ app) which essentially repeated the lab experiment in a large cohort.


Momentary happiness reflects NOT how well things are going, BUT instead whether things are going BETTER than Expected. This includes positive and negative expectations, even in the absence of outcomes.

Rewards received many trials ago have no influence on current happiness in the  task. Recent rewards affected ongoing reactive happiness rating.

Overall effect of expectations on happiness is negative.  i.e.  positive expectations  effectively reduce the overall emotional impact of trials with positive outcomes.Negative expectations, reduce the overall emotional impact of trials with negative outcomes. ( =  if expecting negative outcome, then prepare with more negative expectations to reduce distress later)

Lowering expectations can increase the probability of  positive outcome . ( used in sports= ‘underdog’ approach).However lowering expectations reduce well-being before an outcome arrives.

 A sufficiently negative expectation can help create an overall positive emotional impact from a negative event. ( =predict a longer delay  ( flight/ parcels/appointments) and anything less than that reduce the distress.

Remembered feelings depend most on how experiences were at the   END.  (= painful medical procedures are remembered as less unpleasant when they end with a less painful period).

Phasic dopamine release in striatum is linked to momentary happiness.


Momentary happiness is a result of the combined influence of recent reward expectations and prediction errors arising from those expectations.

Comments: It is not what actually happens that determine how you feel, it is what happened in relation to your expectation that matters.

Summary of the article:

computational and neural model of momentary subjective well-being.

Rutledge RB, Skandali N, Dayan P, Dolan RJ. Proc Natl Acad Sci U S A. 2014 Aug 4

Do initial symptoms predict later remission in schizophrenia? Compre Psy. 2014


Course of schizophrenia is highly heterogeneous. Predicting outcomes in schizophrenia is an extremely difficult task. The popular assumption of rule of thirds” ( in a group of schizophrenic patients one-third improves, one third deteriorates and one third has an intermediate course) do not have an empirical basis.

Some studies  show that 45% to 70% could be defined as remitters at some point during the course of the illness. Shorter duration of untreated psychosis (DUP), a better premorbid adjustment, lower illness severity at baseline, early symptomatic improvement, medication adherence and remitted substance abuse are thought to increase the likelihood for remission.

There are conflicting findings regarding predictability of outcome based on symptoms. Italian researchers Carlo Marchesi and colleagues  investigated whether the severity of positive, disorganized and negative symptoms assessed at onset in first-episode patients with schizophrenia predicted remission (using RSWG criteria) after several years of illness.


56 patients admitted with first episode psychosis between 95-99 were followed up for average of 16 years.  These patients accessed   ‘reasonably comprehensive’ public mental health services. They were re-assessed in 2010  (blind to the baseline evaluation). Of the 56 patents enrolled, 48 were reassessed at follow up. Diagnosis remained same in all at follow up.

38% achieved remission criteria. Among remitted patents (18/48),  3 were in complete symptomatic recovery.

Remission and symptoms at onset: Remitters had milder positive and negative symptoms and a lower overall symptom severity at baseline.

Severity of positive symptoms at onset do not impact on later symptomatic remission. But recurrence of positive symptoms  ( = number of episodes and admissions) during the course of illness could prevent remission.

Negative symptoms remained stable throughout the course of the illness, and exerted a negative effect on the achievement of remission.


Negative symptoms  present at the onset of schizophrenia appear stable and is associated with a poor long-term outcome (i.e. remission. Initial positive symptoms seem to have less prognostic value, but their recurrence during the course of the disorder can impede long-term remission.

Predictors of symptomatic remission in patients with first-episode schizophrenia: a 16years follow-up study.

Marchesi C, Affaticati A, Monici A, De Panfilis C, Ossola P, Tonna M. Compr Psychiatry. 2014 May;55(4):778-84.