How do stress cause psychosis? Epidemiology and Psych Sciences. 2014.Sept

16.10.2014

It is generally recognised that psychosocial stress  play a role in causing mental disorders.  Brown & Burley conducted the first major work looking at stress and schizophrenia in 1960s. Nearly half of those with relapse of schizophrenia had a stressful event in the preceding 3 months. These were later replicated in 1990s. Stress was seen as working with the biological vulnerability in precipitating psychosis.

What are the biological systems that are involved in such stress response?

Mondelli reviews the major findings in this area so far  in this editorial.

1. HPA axis: First episode psychosis patients have increased HPA activation . ( cortisol increased, ACTH high, enlarged pitutary volume, blunted cortisol awaking response ). i.e. axis remain in highly activated state along with reduced reactivity to stress.  These are found to be apparent before the start of psychosis. Increased glucocorticoids can increase mesolimbic dopamine ( in animals). It can also impair neuronal plasticity. Higher cortisol levels lead to hippocampal volume loss. Antipsychotics can reduce the cortisol levels in the day time, but do not change the abnormalities in awakening response.

2.Low magnitude, general and  long-term inflammation: Increased inflammatory status is seen prominently in depression. It is also seen at onset of psychosis. Increase in IL6, TNF alpha, IL-1beta are the most consistent findings. These may be interacting with mono amine synthesis pathways, neuro endocrine systems and neural plasticity. It looks like antipsychotics show an initial anti inflammatory effect but this is followed by a gradual rise in cytokines along with an increase in body weight. So may be it have a direct an indirect effect. higher inflammation is also correlated with poorer outcome in psychosis.

The next questions are 1. Can we use the above biomarkers to predict psychosis among those who face stress? 2. Can it predict who is going to be resistant to antipsychotics? 3. Can we develop new therapeutic options along these pathways?

Comments: Reducing stress and providing support is key in maintaining individuals with psychosis well. At least this is what we can practically offer now. At population level, more awareness & options of support  for all who face stress is crucial. Low key interventions might be useful tools in that.

Summary of the article: 

From stress to psychosiswhom, how, when and why?

Mondelli V. Epidemiol Psychiatr Sci. 2014 Sep;23(3):215-8.

Can we predict bipolar disorder in patients presenting with depression? Jl Aff dis. Oct.2014

13.10.2014

In half of patients who are diagnosed with bipolar disorder, onset episode is one of depression. The proportion is 2/3 in bipolar 2 disorder.Many may have multiple depressive episodes before manic or mixed episode appears facilitating a diagnosis of bipolar disorder.  Predicting who will go on to develop bipolar , if possible, would be huge benefit.

Several factors have been identified previously as associated with a later diagnosis of bipolar disorder in some one  presenting with depression. This include 1.family history of bipolar disorder, (2) cyclothymic or hyperthymic temperament, (3) illness-onset before age 25 years, (4) multiple shorter depressive episodes, (5) stressful precipitants at onset,( 6) presence of ADHD and (7) pathological mood-elevation during treatment with an antidepressant or other mood-elevating agent (stimulant, corticosteroid). Symptoms like prominent agitation, anxiety, psychotic features and atypical symptoms (hypersomnia, hyperphagia, psychomotor retardation) are also suggested as predictors in some studies.

Leonardo Todo  and team from International Consortium for Bipolar Disorder Research ( USA & Italy) report the clinical characteristics that predict later bipolar diagnosis. Of the 2146 patients in an episode of  depression , 30% met criteria for bipolar disorder later. Average time of observation was  around 13 years.

Results

Seven factors were found to be significantly predictive of bipolar disorder.

1. 4 or more depressive episodes before intake 2. suicidal acts (gestures or acts) 3. cyclothymic  temperament 4. First degree family history of bipolar disorder 5. substance abuse 6. younger age of onset 7. male sex. First 4 factors were more strongly associated with later bipolar diagnosis.

if your patient has two factors,  prediction has a sensitivity (71 %) and specificity (62%). i.e.  69% of diagnostic assumption  of bipolar will be correct.

Limitations: all patients did not provide all information about predictive factors, recall of past events may be biased.

Questions like “are unipolar and bipolar two different disorders or two expressions of  one disorder?”  are still hotly debated. Is it that the potential for bipolarity is there at the start of expression of illness or is it a spontaneous change that occurs in the course of illness ( ? due to environmental factors or treatment factors)? The present study does not address these issues, but are relevant for future discussion.

Conclusions: Certain clinical factors can predict the possibility of a patient presenting with depression as eventually diagnosed as bipolar disorder. It is important that clinicians make such assessments to ensure optimum treatments.

Summary of the article:

Bipolar disorders following initial depressionmodeling predictive clinical factors.

Tondo L, Visioli C, Preti A, Baldessarini RJ.

J Affect Disord. 2014 Oct;167:44-9

Would blue lights reduce suicide? Jl Affective disorders. Dec. 2014

10.10.2014

Restricting access to suicide hotspots  is an effective public health intervention. Suicide barrier that is going to be erected at Golden Gate Bridge, San francisco is going to be the costliest suicide barrier in the world. The board has set aside 76 million dollars for this. There are concerns from previous research that substitution ( i.e. increased suicide rates in nearby areas) phenomenon might reduce the effect. AN interesting study from Japan adds to this discussion.

Installation of platform screen doors have shown to reduce metro suicides. In japan, blue lights were installed in some railway stations  and this was found to reduce suicides there. Matsubayashi et al. (2013) showed that blue light installation reduced suicide rate by 83% in the 10 year period. The same group then examined whether substitution phenomenon occurred with this reduction, the results are reported in this article.

They studies the number of suicides at blue light stations and compared this with neighbouring stations ( to see whether there is a shift),They used the number of suicides in all other stations without blue light as the control group.

Results

The updated data still strongly suggest that blue light reduce suicides. Almost no suicides occurred in stations where blue light was turned on in the evening hours. There was no systematic substitution in neighbouring stations. It also shows that blue light has not become less effective over time.

Limitations

Present data only looked at jumping from platform. It is possible that people might choose to jump at railway crossing or they might have chosen to go to a station run by a different company. Suicide rate in the area was not compared  to show whether blue light had an impact on total suicide rate. The effect shown is only for night-time suicide, which accounts for  only 14% of all such suicides.

Comments: Influence of environment in human emotional state is well recognised. Various environmental measures are useful in reducing distress and producing calming effect. It needs to be seen whether such interventions reduce overall suicide rates. It would be interesting to see whether installation of blue lights in acute psychiatric wards have an effect on reducing self harm/aggression incidents.

Summary of the article

Does the installation of blue Lights on train platforms shift suicide to another station?: Evidence from Japan.

Matsubayashi T, Sawada Y, Ueda M. J Affect Disord. 2014 Dec 1;169:57-60

Is lithium augmentation effective in depression? J Aff Dis.Oct.2014

08.10.2014

The 2007 Crossley & Bauer meta analysis clearly showed the benefit of lithium augmentation in depression. The effect size was large as well. (odds ratio  3.11  and NNT of 5). However,  lithium prescription do not reflect this possible benefit.Is it because the original evidence was more for lithium augmentation of TCAs and that we use less of them now a days?

Nelson et al report the results of meta analysis of all studies on this question. They included all double blind RCTS where Lithium or placebo was given after treatment failure with one antidepressant for 21 days ( at least). They identified 13 controlled studies of which 9 met all inclusion criteria. There were 237 patients in total.

Results

OR for response was 2.89. heterogeneity was very  low ( all studies show effect in same direction). Lithium was effective whether it was combined with TCAs or newer antidepressants.NNT for response was 5. The confidence intervals for the OR is wide and hence the true NNT can be between 3 and 9.

Limitations:  Individual studies had small number of patients. ( 8 of 9 trials had fewer than 30 patients). One has to remember that met analytic results of smaller studies can sometimes be misleading.

Comments: Was bipolar status a factor in those who showed response?  There was not enough data to answer this question.

Tolerability of lithium is likely to be a factor in declining use. STARD found Lithium less tolerable than T3. Trials in this meta analysis did not show poor tolerability ( these were shorter trials and hence the tolerability issues may not have appeared).

Atypical antipsychotics as augmenting agents have taken over lithium in actual practice. The database is much larger for that as well.

Conclusion: Lithium is an effective augmenting agent when added to TCA or SSRI.

Summary of the article:

systematic review and meta-analysis of lithium augmentation of tricyclic and second generationantidepressants in major depression.

Nelson JC, Baumann P, Delucchi K, Joffe R, Katona C. J Affect Disord. 2014 Oct 15;168C:269-275.

What predict non response to first line depression treatments? Biol Psy. Oct.2014

06.10.2014

Remission of depression with the first  antidepressant occur in  40% of patients only. Second steps benefit another 15-20%. Lack of response to initial agents usually indicate  a poor outcome.There are many predictors that can help us in choosing a particular treatment. However, for these to be clinically meaningful, these predictors should tell us the possibility of response to a range of treatments that are available rather than to a single agent.

Metabolic activity in right anterior insula has been shown to predict the response to either escitalopram or CBT. The same group (  McGrath et al Emory University) is now reporting predictors of non response two either of these two treatments ( SSRI or cBT). If we can predict who will not respond to these strategies, patents could straight away try some other treatments.

Patients received CBT or Escitalopram for 3 months ( random) and then combined for the next 3 months. Non response= no response over 6 months. Hamilton score 15 or above was needed to be randomised. Those with substance use, medical conditions,psychotic features, suicidal features etch ere excluded. Escitalopram was given 10mg/day with option to increase to 20mg/day. 16 CBT sessions were given.

Results

82 patients were randomised. Phase 1 remission rates were similar (36% for CBT and 40% for  Escitalopram). Baseline Sub Callosal Cingulate (SCC) metabolism was higher in patients who failed to respond to both treatments compared with patients who achieved remission with either treatment. Superior temporal sulcus activity was also increased in the non remitters.

Hyperactivity of SCC was previously reported in resistant depression. Increased connectivity of SCC to default mode network is also reported in recurrent depression. Deep brain stimulation for resistant depression targets this area. All these are converging evidence to suggest that SCC activity is a crucial factor in non response.

Limitations- Patients achieving response were excluded from significance tests. This was because  researchers wanted clear differences in clinical picture and link that to structural/ functional parameters. Small number of participants, need replication.

Conclusions: SCC hyperactivity could be predictor of non response to first line treatments ( SSRI or CBT). if consistently and significantly shown, such predictors may one day help clinicians to fast track patents to most appropriate treatments.

Summary of the article:

Pretreatment brain States identify likely nonresponse to standard treatments for depression.

McGrath CL, Kelley ME, Dunlop BW, Holtzheimer Iii PE, Craighead WE, Mayberg HS.

Biol Psychiatry. 2014 Oct 1;76(7):527-35.

How to treat common side effects of clozapine? Int Cli Psychopharmacol. Nov. 2014

Clozapine has established superiority over other medications in treating resistant schizophrenia.  Clozapine has  many side effects. With appropriate monitoring clozapine is a safe and effective medication. It is important that clinicians have sufficient options to manage side effects that emerge during clozapine treatment.

Roi Sagya, Abraham Weizmana,and Nachum Katza report on the useful treatment options for side effects like hyper salivation, constipation, tachycardia and nocturnal enuresis.

Hypersalivation: This is often a reason for stopping the medication. It occurs in 30-80% of patients. There are medical & social implications .It is thought that swallowing is affected by clozapine ( rather than production). Treatment options: chewing gum ( promote swallowing),head  elevated position  during sleep ( if feeling suffocated), sleeping on side to avoid aspiration are useful strategies. Try to use the minimum effective clozapine dose. Anticholinergics ( biperidine, trihexyphenidyl) , central alpha 2 agonist clonidine or guanfacine can be tried. Remember that these agents can increase constipation and urinary retention.  Atropine ophthalmic drops can be used as mouth wash, this can also be combined with hyoscine. Botulinum injection in to parotid gland has been tried. Sulpiride and amisulpride are thought to reduce salivation. Moclobemide is also suggested as an option. There are no widely agreed guidelines on these various options.

Constipation: Anticholinergic and antiserotonergic effects result in constipation.This can lead to serious complications. Rate of death from constipation is three times than from agranulocytosis. High-fiber diets, proper hydration, and use of stool softeners and laxatives are the usual treatment options. Orlistat, lipase inhibitor, is found to be beneficial in one study.

Tachycardia: This can be related to dose and rate of dose increase. If severe or symptomatic treatment might be needed. Keeping dose low is the first step. Both Atenelol and  Propranalol are effective, atenelol penetrate Blood brain barrier less and is less likely to add to sedation.

Nocturnal Enuresis: Try lowest dose to see whether this disappears. Give less dose at night-time. Restrict fluids, avoid alcohol, coffee etc. Successful treatment with ephedrine, desmopressin,  anticholinergics, tricyclics,  and aripiprazole  are reported. desmopressin can cause hyponatremia.

Summary of the article: 

Pharmacological and behavioral management of some often-overlooked clozapine-induced side effects.

Sagy R, Weizman A, Katz N.

Int Clin Psychopharmacol. 2014 Nov;29(6):313-7.

 

 

Do early social deprivation alter the HPA axis? Psycho neuro endo.Nov 2014

30.09.2014

From animal studies we know that early social deprivation can  make the HPA axis  behave differently . This might be happening through epigenetic modification of the glucocorticoid gene. In rodents, social deprivation up regulate the axis, while in primates it seem to be down regulating it. Normalising social stimulation is found to correct these changes.

What about human experience  of early social deprivation?  Many existing studies are confounded by the inability to separate social deprivation from physical deprivation, malnutrition etc. Koss et al reports the results of an interesting study addressing this question. Would HPA axis behave differently in adopted children?  What factors ( i.e. pre adoptive care related) influence these changes? would these changes explain differences in problem behaviour ?

They compared children raised in families  (53 children) with those adopted out of   institutionalised care (66 children, 18 months- 36 months age at recruitment). A second comparison group  comprised of children (50 children)  adopted internationally from foster care.Children provided daily cortisol samples at roughly 2, 9, 17, and 25 months post-adoption.

Results

The  cortisol levels usually show a steep slope over the day time. Early deprivation and disruption resulted in a LESS  steep cortisol SLOPE  over the daytime hours. This was particularly strong with more social deprivation. This might be due to reduced cortisol awaking response. Adoption did not result in change in this. Parents reported significantly more problem behavior for those adopted from institutions  and those from foster care  and the daytime cortisol slope mediated this finding.

Limitations:This is a convenience sample and has  its limitations 

Conclusion: first longitudinal assessment of daily cortisol production in children as they adapt to their new families. Chronic stress early on in life may have long lasting effect on HPA axis. We need more understanding on the  mechanisms that may have produced this type of down-regulation of the axis.

Summary of the article:

Social deprivation and the HPA axis in early development.

Koss KJ, Hostinar CE, Donzella B, Gunnar MR. Psychoneuroendocrinology. 2014 Aug 7;50C:1-13