Do elevated C-Reactive Protein increase the risk of psychosis? Schiz Bulletin 2014.

04.12.2014

Auto immune disorders and severe infections are risk factors for schizophrenia.  Patients with schizophrenia on average have elevated inflammatory markers. CRP is a commonly measured inflammatory marker, levels are usually below 3 mg/l, but can be up to 10mg/l.  Association with CRP and schizophrenia has been reported in case control studies  in the past.

Marie Kim Wium-Andersen and team from Denmark report the results of  a large prospective study looking at the CRP levels and later diagnosis if schizophrenia.

CPR was measured in two large independent general population cohorts. ( 78810 subjects). They were followed  for up to 20 years .Hospitalisation data was collected from national patient registry.

Results

CRP levels were grouped in to 4 quartiles. Hazard ratios for schizophrenia for individuals in the first quartile were 1.7 (95% CI: 0.3– 8.9) for second quartile, 2.1 (0.4–10) for third quartile, and 11 (2.8–40) for fourth quartile individuals. Ie patients with higher CRP had considerable higher chance of having schizophrenia.

Mean CRP levels were 63% higher for individuals with schizophrenia compared to those without.CRP were associated with a 6- to 11-fold increased risk of late- or very-late-onset schizophrenia, the relationship remained when adjusted for various factors.

A study by Benros ME et al 2011  (with 3.6 million individuals)  have previously shown that auto immune disorders or severe infections ( where CRP is elevated)   increase risk of schizophrenia. CRP might disrupt BBB and increase the permeability for pro inflammatory cytokines and/or autoantibodies.

Limitations: All participants were above age 20 at inclusion, and thus cohort is selective ( late onset schizophrenia only). Severity of disorder was not studied. Cannot exclude that elevated CRP levels per se may be causally associated with schizophrenia.

Summary of the article:

Elevated C-reactive protein associated with late- and very-late-onset schizophrenia in the general population: a prospective study.

Wium-Andersen MK, Ørsted DD, Nordestgaard BG. Schizophr Bull. 2014 ;40(5):1117-27

How to manage agitation in dementia? Br Jl Psy.2014.Dec

02.12.2014

Agitation is a common symptom in dementia. Nearly half of patients with dementia will have agitation symptoms every month and a vast majority will have persistent agitation for long periods.It reduce the quality of life significantly.  Citalopram , Mirtazapine and analgesics seems to have some beneficial effect.Psychotropic use is discouraged  ( antipsychotics and benzodiazepines) as it cause excess mortality and is often ineffective.

The previous systematic review on this topic was done in 2004 and found that sensory interventions were effective. This review looked at evidence for non pharmacological interventions in agitation in people with dementia. Comprehensive search identified 33 RCTs.

Following were the effective interventions

Activities: Activities in care homes reduce agitation. No evidence for activities in severe agitation or outside care home settings. No evidence for long-term effect

Music therapy: Music therapy is effective in reducing agitation. Effect is often immediate.No evidence for severe agitation or outside care homes

Sensory interventions: Massage and multi sensory approaches ( touch, light, auditory stimulation) were effective in acre homes. No conclusive evidence for longterm benefits.

Person centred care: Communication skills training and dementia care mapping training (analysis of behaviour and triggers and interventions to address these) for staff  reduce agitation significantly. Supervision of staff is a key element here.

Limitations:. Most studies addressed agitation in care homes, and effect of such interventions at home is not known. Though authors excluded studies where all participants received medications for behavioural symptoms, cannot assess whether medication use was uneven in different arms.

Strength: Most comprehensive review on this topic.

Conclusions: Non pharmacological interventions are effective in reducing agitation in dementia in care home settings.

Comments: Most of these effective interventions are easily adoptable by care homes.        Most care homes may be already having all these interventions.

Summary of the article:

Non-pharmacological interventions for agitation in dementia:systematic review of randomised controlled trials. Gill Livingston, Lynsey Kelly, Elanor Lewis-Holmes, Gianluca Baio, Stephen Morris, Nishma Patel, Rumana Z. Omar, Cornelius Katona and Claudia Cooper.BJP 2014, 205:436-442.

Is Humour therapy effective? Jl Psych Res. 2014.Epub

27.11.2014

Humour is known to have  positive effects on physical and psychological health. Empirical studies on the use of humour , especially in mental disorder, are lacking.Laughter have physiological ( reduced muscle tension, release beta endorphins) and psychological (create openness, positive mood, reduced rumination, optimism, hope, and positive social support) benefits. Individuals with  psychotic disorders may have defects in recognising humour, but once the meaning is understood,it is observed that the appreciation is intact.

Therapeutic humor is defined  as “any intervention that promotes health and wellness by stimulating a playful discovery, expression, or appreciation of the absurdity or incongruity of life’s situations”.It has been tried in depression and schizophrenia and found to be beneficial (Falkenberg et al.20111)

A structured humour programme  ( using McGhee , 1994) was used to enhance humour skills in a sample of 30 inpatients with schizophrenia. Patients were randomised to recreational therapy( handwork) or humour therapy.  Humour sessions followed a structure: opening fun activity, specific skill introduction, skill practice ,  watching videos and home ‘play’. This was done for 5 weeks.

Results

Humour significantly reduced the negative symptom and  depression scores.

Limitations:  Humour training might help in improving coping abilities, but this has not been studied in this experiment.  How much the skills are sustained and how this will be translated in real life situation is unknown. Effect of humor intervention on outcomes like rehospitalisation is also not known. Small sample size limit the confidence in conclusions.

Comment: It would be interesting to see how humour therapy helps in preventing recurrence in depression.

Summary of the article:

Effectiveness of humor intervention for patients with schizophrenia: A randomized controlled trial.

Cai C, Yu L, Rong L, Zhong H.J Psychiatr Res. 2014 (Epub).

Can human mind control the gene expression? Nat Commun. 2014.Nov.

24.11.2014

Optogenetics has established that light-sensitive proteins can be used to control gene expression. It is also well-known that electrical activity in brain can be converted in to a physical output . Combining these two streams  can  pave the way for new gene and cell based treatments.

Swiss scientists led by Folcher has done exactly that.The work is the accumulation of efforts to control cell gene expressions remotely.Light inducible transgenes  ( that can produce proteins to influence the cell functioning) can be introduced to cells and these can be switched on using light of a particular frequency. What this group has now done is capturing the electrical activity in brain  (electrical activity in brain is already used to control prosthetics) and relay that to a light source which can then switch on the light-sensitive genes.

Researchers created a small, implantable device that contained cells responsive to near-infrared light, and a light-emitting diode  (LED) that produced this wavelength. This was placed under the skin of a mouse. When stimulated by the light, these cells produced a bacterial molecule that induced the synthesis of interferons and these diffused in to animals body. The implant was wirelessly connected to  a monitor that captured a human subjects brainwaves with an EEG sensor placed on their foreheads. Different mental activity of the human participant can produce different EEG signatures. These eeg signatures were then converted to threshold values for stimulating the LED .When the light was turned on, genes within the implant cells were expressed and proteins secreted into the mouse circulation.

What application might this have?

Diseases where brain activity can be distinct and pathological ( e.g. epilepsy ) might benefit from this i.e. the early brain waves are detected and control substance is released by the cells. Chronic pain is another candidate condition. Mental illness?  When brain electrical signature studies reach a stage where differentiation of different mental states are possible, may be then, such devices may regulate neurochemicals or functional circuits to bring the pathological states back to normalcy. But it is a big if..

Summary of the article

Mind-controlled transgene expression by a wireless-powered optogenetic designer cell implant.

Folcher M, Oesterle S, Zwicky K, Thekkottil T, Heymoz J, Hohmann M, Christen M, Daoud El-Baba M, Buchmann P, Fussenegger M. Nat Commun. 2014

Is Saffron as good as fluoxetine? Human psycho pharm. 2014.Nov

17.11.2014

Saffron is the dried  stigmas and styles of the saffron flower (Crocus sativus L.). It is  the most expensive spice in the world. Saffron has been used as an anticonvulsive, analgesic, aphrodisiac and antispasmodic in traditional medicine. Pharmacological studies have shown that it may have anticancer, anti-inflammatory, antioxidant and anti platelet effects. A recent meta-analysis, was confirmed to be effective for the treatment of depression (Hausenblas et al., 2013).

What are the underlying mechanisms that make saffron an antidepressant?

Lopresti &  Drummond explores the evidence for saffrons antidepressant action and describes possible mechanisms in this article.

Actions:

1. Constituents of saffron like   crocin, crocetin and safranal, are potent antioxidants. Depression is associated with lowered antioxidant enzymes and elevated oxidative stress. The antioxidant action is high  when  the above three constituents are delivered collectively.

2. Crocin and crocetin  in saffron is shown to have strong anti-inflammatory activity. Depression is associated with inflammatory disorders. Inflammatory markers like C-reactive protein , interleukin-6 , and tumour necrosis factor-α are repeatedly shown to be higher in depression. Cytokine therapy is known to increase depression. Some anti-inflammatory agents have antidepressant action. Some antidepressants have anti-inflammatory action.

3. Evidence of saffron’s action on serotenerigic system is lacking

4.  Saffron might have a role in lowering the HPA response to stress, there is limited preliminary evidence to support this.

5. Saffron have some neuroprotective effect .It can increase BDNF.

4 published RCTs suggest that in mild moderate depression saffron is as effective as fluoxetine or imipramine. The effect size in 2013 metaanlysis was 1.62. The dosage used was 30mg/day. Daily dose up to 1.5 gm is considered safe.  Authors caution  use in individuals with coagulation disorders.Long term efficacy is not been studies beyond 8 weeks.

It appears that it is a promising option in mild to moderate depression. Studies on severe depression and for longer periods are lacking. Trials has not been conducted outside Iran.  Larger clinical trials with long-term follow-ups are needed before firm conclusions can be made regarding saffron‘s efficacy and safety for treating depressive symptoms.

 Author  (AL)has declared that he has shares in a neutraceutical company.

Summary of the article:

Saffron (Crocus sativus) for depression: a systematic review of clinical studies and examination of underlying antidepressantmechanisms of action.

Lopresti AL, Drummond PD.Hum Psychopharmacol. 2014 Nov;29(6):517-27

Do proton pump inhibitors increase the risk of dementia? Eur Arch Psychiatry Clin Neurosci. 2014. (ahead of print)

14.11.2014

Global prevalence of dementia is increasing. Estimated cost of dementia worldwide in 2010 was US$604 billion. It is thus important to consider all factors (especially those preventable ones) that might be contributing to cause dementia. Proton pump inhibitors (PPIs: Omeprazole and other prazoles) are widely used medications, Many countries record many fold increase in PPI prescription over the last decade. Many  such prescriptions are considered inappropriate.  PPI can cause Vit B12 deficiency and this may contribute to cognitive decline. They can also affect the brain enzymes like b- and c-secretase which can lead to increased Amyloid beta levels.

Britta Haenisch et al looked at the correlation between PPI use and developing dementia in a German elderly population sample over 6 years.Information from 3,327 participants from  German dementia research database were analysed. These were patients 75 or older with no dementia at entry to the study. Potential confounders like  age, sex, education, polypharmacy, and the comorbidities depression, diabetes, ischemic heart disease and stroke, and the Apolipoprotein E4 (ApoE4) allele status were also studied. 3,076 subjects were included in this analysis.  713 patients received a PPI during the study period.

Results

Use of PPIs was associated with a significant increased risk of dementia [hazard ratio (HR) 1.38, 95 % confidence interval (CI) 1.04–1.83; p = 0.02). As expected presence of an ApoE4 allele (2.25), depression (HR 2.28), diabetes, and stroke showed a significant increase in risk of incident dementia.

Limitation: whether PPI was taken regularly is known in follow-up 3 and 4 only. Statistical association is shown- biological  mechanisms to be understood.

Conclusion: This is the first epidemiological investigation showing evidence that PPI use might have an impact on dementia risk. Among primary care patients aged 75 years and older the use of PPIs was associated with a significant increase in the risk of incident dementia.

Summary of the article:

Risk of dementia in elderly patients with the use of proton pump inhibitors.

Haenisch B, von Holt K, Wiese B, Prokein J, Lange C, Ernst A, Brettschneider C, König HH, Werle J, Weyerer S, Luppa M, Riedel-Heller SG, Fuchs A, Pentzek M, Weeg D, Bickel H, Broich K, Jessen F, Maier W, Scherer M. Eur Arch Psychiatry Clin Neurosci. 2014 Oct 24. [Epub)