A ‘magic’ moment in treating resistant depression?

Psilocybin is a prodrug of Psilocin , a classic psychedelic drug. It is a non selective serotonin agonist ( 2 A receptor). Psychedelics like LSD and Psilocybin were investigated as therapeutic agents in 1960s. Regulatory restrictions prevented assessing therapeutic potentials of these agents. An increasing interest in these possibilities has emerged in the past decade.

 A recent systematic review supported the idea that such agents can be of some benefit in those with anxiety and depression in the context of life threatening disorders (Reiche et al 2017).  If provided with psychological support ,psychedelics are useful in a range of psychiatric conditions (like end of life anxiety, OCD and some addictions). There is growing interest in psychedelic assisted psychotherapy as well. These agents also have anti-inflammatory properties which may also be of significance in treating many inflammatory disorders of neurological system. ( Nichols, 2017)

Robin L Carhart-Harris and colleagues from UCL  wanted to see how brain function changes when psilocybin is given to individuals with resistant depression.  This is the first study that documents  changes in resting-state brain blood flow and functional connectivity post-treatment with psilocybin for treatment-resistant depression. 19 patents with resistant depression participated in this. They  had f MRI before and after the intervention. Two doses of Psilocybin were given one week apart ( 10mg and 25 mg). Arterial spin labelling (ASL) and blood oxygen level dependent (BOLD) resting state functional connectivity (RSFC), were used to measure changes in cerebral blood flow (CBF) and functional connectivity.

Good antidepressant response with Psilocybin :

The mean depression score (QIDS-SR16) for the week prior to the pre-treatment scan was 16.9 ± 5.1, and for the day of the post-treatment scan, it was 8.8 ± 6.2 (change = −8.1 ± 6, p < 0.001).The mean QIDS-SR16 score at baseline (screening) was 18.9 ± 3, and for 5-weeks post-treatment, it was 10.9 ± 4.8 (change = −8 ± 5.1, p < 0.001). All showed some decrease in depressive symptoms at 1 week, with 12 meeting criteria for response . All but one patient showed some decrease in QIDS-SR16 score at week 5 (with one showing no change) and 47% met criteria for response (change = −9.2 ± 5.6 p < 0.001).

Brain correlates of improvement :

Increased RSFC was observed within the default-mode network (DMN) post-treatment.

Reduction in amygdala blood flow was associated with clinical improvement. Increased ventromedial prefrontal cortex & bilateral inferior lateral parietal cortex RSFC was predictive of treatment response at 5-weeks. Decreased parahippocampal-prefrontal cortex RSFC was also predictive of treatment.

Patients scoring highest on ‘peak’ or ‘mystical’ experience had the greatest decreases in para hippocampal RSFC in limbic (e.g. bilateral amygdala) and DMN-related cortical regions.

Acute effects Vs post acute effects :

 Brain activity observed just one-day after a high dose psychedelic experience are very different to those found during the acute psychedelic state . Previous studies have shown decreased DMN integrity under psilocybin ( i.e. acute effect). In this study, increased DMN integrity was observed one-day post treatment with psilocybin. Psilocybin dysregulate cortical connectivity acutely,  and then create a state of enhanced connectivity ( ‘entropic’ brain state / ‘desegregation’= ‘ego dissolution/’openness’). In this regard, we can see some similarities with ECT, where DMN integrity is decreased acutely, followed by a strong normalisation effort resulting in increased coherence/ integrity post acutely. This later changes are related to improvements in mood.


This study is limited by its small sample size and absence of a control condition. Larger studies with placebo/ control conditions and longer follow up would be required to establish these exciting positive effects.

Summary of the article: 

Psilocybin for treatment-resistantdepression: fMRI-measured brain mechanisms.  Robin L Carhart-Harris et al. http://www.nature.com/scientific reports. 13 October 2017.


Do Statins have antidepressant effects?

Evidence supporting  inflammatory etiology of depression is gaining strength. Inflammation is considered as an operative pathway that links physical disorders with depression. The role of statins in depressive disorders is an interesting one in this context. Statins have become the best selling medication in the history  and hence it is important to know their effects on mood disorders.

Statins inhibit the enzyme HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis in the liver. CVD preventive effects of statin is seen more in those with raised CRP levels to the extent that some authors suggest that CRP is a better marker of CVD preventive effects of statins. Various observations like this suggest that statins have anti-inflammatory properties.

Statins as antidepressant augmenting agents 

In the last 4 years, attempts have been made to see the antidepressant effect of statins. (examples: Ghanizadeh 2013, Haghighi 2014, Gougol 2015 ). All these studies show that adding statin to SSRI augments the antidepressant response significantly. A meta analysis by Salagre et al 2016 confirms these findings. (standard mean difference (SMD) of -0.73; 95% CI -1.04 to -0.42; p \ 0.001)

Statins prevent depressive relapses?

The above experimental findings are supported by epidemiological observations as well. A notable study is the Danish one ( Kohler et al 2016) with 800,000 plus patients showing  that combined treatment with an SSRI and a statin was associated with a 36% decreased risk for hospitalization with depression (hazard rate ratio of 0.64; 95% CI 0.55–0.75) compared with treatment with an SSRI only.

Do statins have primary preventive effects?

Meta analysis of seven observational studies found that statin users were 32% less likely to develop depression compared with non-users (Parsaik et al 2014). Another meta analysis showed that those on statins are better in their mood states. (O’Neil et al 2012). But all observations studies are limited by confounders.

Is there risk of depression if LDL levels are too low?

Among elderly , there is some evidence to suggest that statin may cause cognitive decline and depressive symptoms. An inverse relationship  between LDL cholesterol and depression is suggested ( Mandas et al 2014). Previous reports of suicidal ideation and low cholesterol has been contested in later studies. However, it might still be that, severe depletion of cholesterol may have effects on membrane lipids that are crucial in syntactic signalling.

Class effect ?

It appears that statins observed effects in depression is a class property. However, some epidemiological studies show some difference between agents as well. It might be linked to their ability to cross BBB (for example, atorvastatin crossing easily than others).  The subgroup with higher CRP levels may respond better to combination of statin and SSRI. There is some suggestion that if CRP is elevated, tricyclics might be even more effective. However, this has not been studied yet.


Studies suggest that statin have anti-inflammatory property independent of  lipid lowering effect. This may explain the anti depressant like effect seen when added to SSRI. Factors like inflammatory markers, genetics, type of depression, Cvd comorbidity may impart differential effects. In general, evidence suggest that statins can be helpful in depression.


Further reading:


Do Statins Have Antidepressant Effects? Köhler-Forsberg O, Gasse C, Berk M, Østergaard SD.CNS Drugs. 2017 May;31(5):335-343

Interactions between pro-inflammatory cytokines and statins on depression in patients with acute coronary syndrome.Kim SW, Kang HJ, Bae KY, Shin IS, Hong YJ, Ahn YK, Jeong MH, Berk M, Yoon JS, Kim JM.Prog Neuropsychopharmacol Biol Psychiatry. 2017 Jul 6

Statins for the treatment of depression: A meta-analysis of randomized, double-blind, placebo-controlled trials.Salagre E, Fernandes BS, Dodd S, Brownstein DJ, Berk M.J Affect Disord. 2016 Aug;200:235-42. doi: 10.1016/j.jad.2016.04.04

Internet and Youth suicide: What do we know?

It is not surprising to observe that internet exerts positive and negative influences over its users. There are increasing concerns over its effect on teenagers and their mental health.  Cyber bullying and self harm are two prominent issues in this regard. Scientific enquiries  are gradually exploring these issues .

Marchant, Hawton & Stewart  et al comprehensively  reviewed  the potential influence  of the internet on self-harm/suicidal behaviour in young people. This systematic review covered all publications that primarily studied internet use by individuals who experienced suicidal ideation, self-harm, or internet use which was clearly related to self-harm content among users under 25. 51 articles were included in this review. A total of 192,950 individuals participated across these studies.


High internet use and internet addiction appear to have largely negative influences. More than two or five hours per day ( different studies) were associated with suicidal ideation.

Self-harm and suicidal ideation were related to searching online for suicide information and that searches for specific methods were related to rates of suicide in young people

Positive influences included lower levels of loneliness.  A potential protective influence of low levels of internet use when compared with no internet use at all was also reported.

Health professionals expressed discomfort about engaging with young people in an online setting and had concerns over duty of care.

Specific processes ( harmful)  related to internet use:

  1. Normalisation
  2. Glorification
  3. Competition:  triggering and competition between users
  4. Contagion
  5. Information resource:  Harmful information sources for vulnerable individuals

Specific processes ( helpful)

  1. A sense of community
  2. Crisis support
  3. Reduction of social isolation


Several major social media platforms  have  implemented policies regarding posts related to self-harm ( Such content may not be searchable, is banned or brings up links to counselling and prevention resources).

On the background of the ‘blue whale challenge’ widely reported in many media, the statement from European Psychiatric Association ( suicidology section) is worth reflecting on. …..Anyway, actually we really don’t know either the game’s existence or its role in child and teenage suicides or acts of self-harm…. Professor Sonia Livingstone from the London School of Economics told WIRED: “The importance of media literacy to identify and reject fake news is vital for everyone, but especially for parents whose anxieties about their children’s safety make them too easily to fall prey to clickbait designed to trap them. The responsibilities of journalists to check their facts and sources has also never been so great, as the Blue Whale scare illustrates clearly.”,…..

Nonetheless, the implications of the phenomenon are important, at least from the sociological point of view, no matter if it is a false news or it is proven in some cases……

…..Every alarming news, every service that drives the macabre storytelling, every act of self-harm and violence automatically may fuel a vicious cycle of suggestion and discomfort……


Human embroidery’ is now a new ‘self harming art’ that is slowly spreading in China.  The need to show , share , shock and scare is taking an ever  prominent place in our lives. This might be a ‘minority’ phenomenon , but its ‘ normalising’ effect can be huge.

It is important to protect children from online dangers and also let them know the existence of support networks involved in offering help to people who need it…..Health departments should take initiative to create online resources and confidential support networks .

Summary of the article.

A systematic review of the relationship between internet use, self-harm and suicidal behaviour in young people: The good, the bad and the unknown.

Marchant A, Hawton K, Stewart A, Montgomery P, Singaravelu V, Lloyd K, Purdy N, Daine K, John A. PLoS One. 2017 Aug 16;12(8):e0181722. doi: 10.1371/journal.pone.0181722. eCollection 2017.


Can vegetarian diet make men more unhappy?

Vegetarians generally enjoy a lower risk of cardiovascular disease, diabetes, obesity and some cancers. However, effect on mental health , as far as we know , seems to suggest a different story.  Among Australian women, depressive symptoms were more reported among vegetarians (Baines et al 2007). Another study , again from Australia, showed that lower end meat consumption was associated with doubling the risk of depression and anxiety (Jacka et al 2012). Similar findings were reported from Norway , Germany and Turkey  ( Larssson et al 2001, Michalak et al 2012 etc). It is possible that vegetarian diet may have less Iron, Zinc, Vit B12 and Omega 3 compared to non vegetarian diet and this may explain the observed associations.

JR Hibbeln and colleagues studied whether self-identification of a vegetarian diet was associated with increased risk of depressive symptoms among adult men during the pregnancy of their partners.

Self-report data from 9668 adult male partners of pregnant women in the Avon Longitudinal Study of Parents and Children (ALSPAC) is analysed to see whether diet is associated with depressive symptoms. ALSPAC is an ongoing population based cohort study, based in Avon in the UK, investigating environmental and other influences on the health and development of children. Men completed  the Edinburgh Postnatal Depression Scale (EPDS) as part of assessments of the pregnant women who were recruited to this cohort. Comprehensive background data for these men were also collected.


Multivariate analysis suggest that factors like housing tenure, number of children in the household, religion, family history of depression,alcohol consumption, marital status and employment status were independently associated with depressive symptoms. Vegetarians show more depressive symptoms after adjusting for all the above factors. When EPDS scores were converted to binary variable the association still held positive. Elevated odds ratio for an EPDS score greater than 10 and vegetarianism was 1.71 (95% CI: 1.17, 2.49; p = 0.005).

This is the first large epidemiological study to show a relationship between vegetarian diet and significant depressive symptoms among adult men. The increased risk of depressive symptoms is seen when symptoms are evaluated either as a continuous scale or while using a cut-off of greater than 10 on the EPDS. This association persists even after adjusting for all other known vulnerability factors.

Possible explanations

1. Vegetarians have lower intake of omega 3, Vit B12 and folate . They may be taking more omega 6 (from nuts). Veg diet may be associated with increased intake of phytoestrogens, and possibly more of metabolites of pesticides.

2. It is possible that vegetarians were making a dietary  choice because they had to reduce weight / and or may have medical conditions that prompted them to do so. Such medical conditions may be associated with depression.

4. Vegetarianism MAY BE  an expression / marker of psychiatric/ personality problems in certain populations where vegetarianism  is not the norm. Dissatisfaction with one’s body is a frequent theme among adolescents who adopt vegetarianism in a meat preferring eating culture.


No serum levels of nutrients collected in this study.

Reverse causality cannot be completely ruled out.

Vegetarian status was self identified rather than based on food frequency questionnaires. It is known that many self identified vegetarians are found to consume non vegetarian food when detailed dietary habits are collected.


High meat consumption  is also shown to be associated with depressive symptoms. Such unhealthy dietary patterns often go hand in hand with physical inactivity, smoking and alcohol consumption. It needs to be seen whether the observed  association between vegetarian diet and depressive symptoms holds true in populations where vegetarianism is the main stream dietary practice.

Summary of teh article:

Vegetarian diets and depressive symptoms among menHibbeln JR, Northstone K, Evans J, Golding J. J Affect Disord. 2017 Jul 28;225:13-17. doi: 10.1016/j.jad.2017.07.051. [Epub ahead of print] PMID: 28777971

New rapid acting medication for post partum depression

Depression in the post-partum stage is seen in 10-20% of all mothers. It is a leading cause of maternal mortality and has long standing negative consequences on the child. Changes in plasma allopregnanolone ,especially the abrupt decrease post-partum, is linked to the precipitation of depression 2.  Plasma allopregnanolone is a neuro active steroid with potent positive modulatory effect on extra synaptic GABA receptors. Rapid metabolism and poor bioavailability prevent the use of the oral form of allopregnanolone. Brexanolone , an intravenous  formulation of allopregnanolone, is showing promise in the treatment of post-partum depression.3

Kanes et al., carried out a randomised double blind, parallel group placebo controlled study across four sites in USA.3 Twenty-one women with severe depression ,within the initial 6 months period post-partum, participated in this study. A single continuous IV infusion of Brexanolone was administered for 60 hours . Outcome Assessments were done on day 30. At the end of 60 hours, the HAMD total score decreased by 21 points in brexanolone group compared with 8.8 points in placebo group. This was more or less maintained up to day 30 (the study end point). At 60 hours, seven out of ten patients receiving brexanolone met remission criteria compared with one in placebo arm.  On day 30, seven patients reached remission on active treatment compared to two with placebo. The medication was well tolerated. Overall side effects were higher in the placebo arm. Tachycardia, sedation, and dizziness were reported with brexanolone.

This study provides the first robust evidence of the effectiveness of brexanolone, an extra synaptic GABAa receptor modulator, in treating post-partum depression. The rapid onset of action is particularly useful given the serious impact (e.g., disrupted bonding)  of the illness on mother and baby . This is a promising start and if replicated is likely to find its way into clinical practice, given the key role played by post-partum depression in maternal mortality.


  1. Balon R. Has psychopharmacology entered a blind alley? Ann Clin Psychiatry Off J Am Acad Clin Psychiatr. 2017 Aug;29(3):157–8.
  2. Nappi RE, Petraglia F, Luisi S, Polatti F, Farina C, Genazzani AR. Serum allopregnanolone in women with postpartum “blues.” Obstet Gynecol. 2001 Jan;97(1):77–80.
  3. Kanes S, Colquhoun H, Gunduz-Bruce H, Raines S, Arnold R, Schacterle A, et al. Brexanolone (SAGE-547 injection) in post-partum depression: a randomised controlled trial. Lancet Lond Engl. 2017 Jun 12; doi: 10.1016/S0140-6736(17)31264-3.

Why we should stop using sodium valproate …

France has decided to ban use of sodium valproate among women who are of child bearing age group and not on any efficient contraception. At the moment this applies only for those with bipolar disorder. They wanted to do the same for epilepsy as well, however, lack of alternatives have stopped France from banning it for this indication as well. It is contra indicated in pregnancy for both  epilepsy and bipolar disorder in Australia and New Zealand. Most countries have strict guidelines on prescribing valproate in women of child bearing age group.   It is expected that EU would soon ban valproate prescription for women of childbearing age group following French example.

Valproate is the most teratogenic drug around. Up to 40% of pre school children exposed to valproate in utero have developmental problems. Risk of autism is five times in this group. Risk of malformations is 12% compared with 2-3% in general public.

Valproate victims in France is preparing a class action suit  against the pharma giant Sanofi.Sanofi is refusing to acknowledge  its responsibility or the causation. It is expected that 30,000 children would have to be compensated and the total bill would be more than 400 million euros.

In countries where guidelines are not strictly followed or prescriptions  monitored,  many women could be exposed to these serious risks. Prescribers need to be extra vigilant on these risks and consider alternative medications.

France bans sodium valproate use in case of pregnancy.

Casassus B. Lancet. 2017 Jul 15;390(10091):217. doi: 10.1016/S0140-6736(17)31866-4. No abstract available.





Nine modifiable risk factors for dementia

Dementia is the greatest challenge for health and social care in this century. What can individuals and societies do to prevent dementia ?  

The Lancet commission on Dementia reviewed this question in its report published this week in Lancet ( online , July 20). The word dementia has demeaning connotations and DSM has replaced it with the phrase ‘ major neuro cognitive disorders”. The present report uses the word dementia to cover all types of dementing disorders.

Dementia Decreasing? :  Some countries have noticed an age specific decrease in dementia prevalence/ incidence. This is attributed to an increase in education.  However, many societies would see increase in dementia due to increasing mid life rates of obesity and associated ill health.

We know that vascular / metabolic factors , diet, life style, education and mental health are  the key modifiable risk factors here. However, the greatest risk factor, age is unmodifiable.

Cognitive reserve: Those with more brain reserve can tolerate more neuropathology without much cognitive and functional decline. At population level, access to reserve enhancing factors ( like physical exercise, intellectual stimulation, leisure activities ) over  life span can reduce the risk of dementia.  Hypertension can reduce the cognitive reserve and thus increase the risk of dementia. Cognitive resilience in later life is associated with healthier life styles, higher education and improved socio economic status during early childhood.

Population Attributable Risk 

This review identified 9 modifiable risk factors. 35% of dementia is attributable to these factors. For example: We can see that if no one in above 65 age group is smoking, this will eliminate 5.5% of dementia in the population.

Risk factor Relative Risk (RR)  Pop. Attributable Factor (PAF)  (Weighted)
1.Less education 1.6 7.5%
2.Hypertension 1.6 2%
3.Obesity 1.6 0.8%
4.Hearing Loss 1.9 9.1%
5.Smoking 1.6 5.5%
6.Depression 1.9 4%
7.Physical inactivity 1.4 2.6%
8.Social isolation 1.6% 2.3%
9.Diabetes 1.5% 1.2%

Factors 2, 3 and 4 are Midlife ( 45-65) risk factors . Factors 5,6,7,8,9 are later life risk factors. To see the PAF in perspective, you may want to see how much reduction in incidence of dementia will happen if   apolipoprotein E4 allele is completely eliminated. This would bring  7% reduction at population level. If every one had good education (up to secondary level), this would bring the same population benefit.

One interesting finding is the risk due to hearing loss.The RR is highest for this factor. It is estimated that one third of all aged above 55 have some degree of hearing loss.  Microvascular pathology may be a confounding factor here. Whether hearing corrections reduce this risk is not known at this moment.

What are the evidence based  prevention strategies? 

1.Treating hypertension is shown to reduce the risk of dementia

2.NSAID and statins do not reduce the risk. HRT is also not recommended for this benefit.

3. Mediterranean Diet: Possible positive effect . Reduce cognitive ageing.

4. Cognitive interventions: Engaging in cognitively stimulating activities can improve cognition and reduce dementia

5. Physical exercise improves cognition, but evidence to reduce dementia is lacking

6. Not much is known about the effect  of social activities on risk reduction.

What about high risk group interventions?

The FINGER study was a mammoth undertaking to provide 4 intensive life style based interventions (diet, exercise, cognitive training, vascular management ) to 600 participants over 2 years. General cognition did improve , but there was no difference in memory when compared with controls. PreDIVA study ( Netherlands) showed that vascular risk factor management for elderly  did not reduce the dementia incidence over 6 year period.

The current evidence base (from clinical trails)  is unclear  regarding  specific interventions at population level that would reduce the dementia risk. Despite this, risk factor understanding  is pointing towards the need to implement  safe interventions that confer general  health benefits. Increasing education in early life, increasing physical activity and social engagement, reducing smoking, treating hypertension , depression, diabetes, and hearing impairment should be our priorities.

Summary of the article

Dementia prevention, intervention, and care.

Livingston G, Sommerlad A, Orgeta V, Costafreda SG, Huntley J, Ames D, Ballard C, Banerjee S, Burns A, Cohen-Mansfield J, Cooper C, Fox N, Gitlin LN, Howard R, Kales HC, Larson EB, Ritchie K, Rockwood K, Sampson EL, Samus Q, Schneider LS, Selbæk G, Teri L, Mukadam N.

Lancet. 2017 Jul 19. pii: S0140-6736(17)31363-6. doi: 10.1016/S0140-6736(17)31363-6. [Epub ahead of print] Review




institute for mind and brain ( inmind hospital ), Thrissur, Kerala.