Is cognitive function related to plasma ratio of Clozapine to N-Desmethylclozapine? AM J Psych.June,2015


Working memory is defective in patients with schizophrenia. Poor working memory is associated with poor functional outcome. Though muscarinic neurotransmission is postulated to play a significant role in this, improving cholinergic transmission do not seem to improve working memory. Large individual variability in cholinergic status is mentioned as an explanation. clozapine also show a range of effects on cognition ( improve, neutral, deleterious effect on cognition). Is this difference due to differential actions of clozapine and its metabolite,  N-des methyl clozapine (NDMC)?

Clozapine has antimuscarinic actions at M1,M3 and M5 while NDMC is a potent partial agonist at these sites. Plasma concentrations of NDMC can vary from 20% to 150% of clozapine concentrations. It is likely that the ratios clozapine and NDMC will have an effect on cholinergic tone and thus on cognition.

Tarek K. Rajj et al from Toronto explored the relationships between serum anticholinergic activity (SAA), clozapine concentration, NDMC concentration, and cognition. 30 adult patients with schizophrenia/ schizoaffective disorder on stable clozapine monotherapy  participated in this study.Cognition was assessed with the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB).


Working memory  was negatively correlated with clozapine/NDMC ratio. Working memory   was not correlated with age, gender, education, PANSS score, clozapine concentration, or NDMC concentration. SAA levels correlated with clozapine level but not with working memory.The association between clozapine/NDMC ratio and cognition is specific to working memory,

Limitations: This is cross sectional study. We do not know the baseline cognitive functioning of the participants. Duration of treatment with clozapine is another factor to consider,as benefits of clozapine may not be accrued if less than 6 months.

Comments: This opens several interesting clinical possibilities and precautions.  If we can inhibit the metabolism of NDMC, ( but not clozapine ) we can expect improvement in working memory. Patients with high clozapine /NDMC ratio would need special attention, they may have more working memory problems and can also experience  delirious states.

Summary of the article: 

Prediction of working memory performance in schizophrenia by plasma ratio of clozapine to N-desmethylclozapine.

Rajji TK, Mulsant BH, Davies S, Kalache SM, Tsoutsoulas C, Pollock BG, Remington G.

Am J Psychiatry. 2015 Jun 1;172(6):579-85.

Do risk of dementia increase substantially when depression and diabetes occur together? JAMA Psych. June, 2015.

16 06 2015

Diabetes (DM) affects up to 14% of Western population. 25% of women and 16% of men will have  depression during their life time. Depression and diabetes  often co occur . The link between DM and depression is bidirectional. It is also known that both disorders contribute to an increased risk for vascular complications.

Depression and DM – both are  strong independent risk factors for dementia. DM increase risk for all cause dementia by 47%. Depression  doubles the subsequent risk for all-cause dementia. What about the combination of DM and depression?
Studies on patients with DM have shown that those who also have depression are at a high risk of dementia. Further clarity on this would be gained if large cohorts of individuals could be studied for risk for all-cause dementia among persons with DM, depression, or both compared with persons who had neither illness.

A Danish study ( by researchers from Seattle and Copenhagen) using national cohort of 2.4 million people has done just this.All living Danish citizens 50 years or older who were free of dementia at January 2007  were followed up until  December, 2013 .Danish psychiatric central register identified individuals with a diagnosis of depression or who have been prescribed with antidepressants. National diabetes register identified those diagnosed with DM .


19 % had a diagnosis of depression. 9 % received a diagnosis of DM, and 4%  had  comorbid depression and DM.The mean age at the initial diagnosis of DM was 63  years. Mean age  at the initial diagnosis of depression was 59  years. 2.4% developed  dementia, of this, 26% had depression alone,11% had DM alone, and 7%  had comorbid depression and DM.

Depression alone, contributed  83% greater risk of dementia. DM alone was associated with a 20% greater risk for all-cause dementia.  Depression and DM the risk was higher:  a 117% greater risk. This combined effect is more pronounced  in younger people. The combined effect of these two  illness exposures on all-cause dementia risk was larger than the sum of the 2 individual diseases.

One  limitation is  the lack of information on possible confounders such as health-risk behaviors ( smoking, obesity, and sedentary  lifestyle) .These can well be mediators of the association.

Comments: Depression alone is associated with the highest relative risk for all-cause dementia. Individuals with depression and DM need to consider engaging in neuro protective activities.  Physical activity is  increasingly well established as an effective strategy. It have  anti-inflammatory effects and it promotes  neurovascular health.

Summary of the article:

Effect of depression and diabetes mellitus on the risk for dementia: a national population-based cohort study.

Katon W, Pedersen HS, Ribe AR, Fenger-Grøn M, Davydow D, Waldorff FB, Vestergaard M.

JAMA Psychiatry. 2015 Jun 1;72(6):612-9

Do brain cortical thickness differ according to income ? Psychological Science.June, 2015

15 06 2015

Educational achievement is highly correlated with socio economic status. The difference in academic achievement between students from higher and lower income groups  (income achievement gap) is increasing in many countries. There are various ( social, psychological, biological) reasons for this. Are there neuroanatomical differences between higher and lower income children ? Do these differences explain the income achievement gap?

Allyson P. Mackey and team of researchers from USA related cortical structure parameters ( cortical grey and white matter volumes, cortical surface area)  to family income and performance on standardized tests of academic skills. Eligibility for free/ reduced price lunch at school was the criterion for classifying as poor SES. Participants, 58 school children ( 15 yrs age on average) participated in this study. They completed Massachusetts Comprehensive Assessment System (MCAS) for academic performance measure.All underwent MRI to measure the cortical parameters.


Academic performance scores were significantly lower in lower income group.Cortical gray-matter volume was significantly greater in the higher-income group than in the lower-income group. Cortical thickness in all lobes of the brain was greater in students from higher-income than lower-income backgrounds. Greater cortical thickness, particularly in temporal and occipital lobes, was associated with better test performance. Cortical white-matter volume and total cortical surface area did not differ significantly between groups.

It is possible that these differences are due to less gray-matter formation early in development  or could be due to accelerated thinning. Higher levels of stress and less enrichment in the environment may have influenced brain development.

It needs to be highlighted that a thicker cortex is not inherently better. relationship between cortical thickness and cognitive performance is still unclear. Educational interventions in lower income children have proven to enhance performance as well as neural connectivity.

comments: It is well established that income and SES play a crucial role in academic achievement. Growing body of research indicate that brain suffer from inequality and poverty in many different ways.

Summary of the article:

Neuroanatomical correlates of the income-achievement gap. Mackey AP, Finn AS, Leonard JA, Jacoby-Senghor DS, West MR, Gabrieli CF, Gabrieli JD. Psychol Sci. 2015 Jun;26(6):925-33

Is inhalation antipsychotic safe and useful? Annals Gen psych. 2015.April.


Controlling acute agitation early on is important to avoid serious and harmful consequences. Oral and IM medications are the main pharmacological routes available now to achieve this. Inhalation route is another possibility opened with the licensing of the first inhalation antipsychotic medication.

Loxapine is a typical antipsychotic in use since 1970’s. It is  widely used in France and Canada. Inhalation form is approved  ( US & EU) for acute treatment of agitation in adults with schizophrenia / bipolar disorder. Maximum plasma concentration is achieved in approximately 2 minutes. Half-life for the 5- and 10-mg doses is approximately 6 hours.

Dina Popovic, Philippe Nuss and Eduard Vieta review efficacy and safety of  loxapine in this article.

Loxapine is structurally similar to clozapine. It has actions on D2 as well as 5 HT 2A receptors. It has atypical characteristics. A 2007 Cochrane review showed that loxapine  ( oral) is as effective as other typical and atypical antipsychotics. As expected,  EPS is the main side effect of medications like loxapine. There have been no trials assessing the efficacy of the oral or intramuscular formulation of loxapine in acute treatment of manic episode, but is still widely prescribed in the treatment of mania.

Effect on  acute agitation ( inhalation loxapine)

In two phase III studies (one in subjects with schizophrenia, the other in subjects with bipolar disorder) inhaled loxapine doses of 5 and 10 mg were both superior to placebo 10 min after administration. Pooled data suggest  that NNT  is  comparable to that observed for intramuscular administration of other antipsychotics.

Interestingly,  no clinically relevant extrapyramidal side effects or akathisia have emerged following administration of loxapine 10 mg or 5 mg. There is no apparent QT prolongation . Most common adverse event was short-term dysgeusia.

 Active airways disease (asthma and chronic obstructive pulmonary disease)  is a contraindication due to the risk of bronchospasm .

Limitations:  Data sets available are small .  The inhaler is single use only . The recommended use of  10 mg administration ( only a single dose  in 24 hrs) raises the issue of further medication choices if agitation is not controlled. Screening for chest conditions  ( including auscultation ) may be difficult when patients are agitated. 

Comments: If  the favourable side effects profile is established in large data sets, loxapine inhalation may be a preferred  option in early stages of agitation in cooperative patients.  This is particularly the case as ECG is  recommended/ required before administering  haloperidol, which is   commonly used to control agitation.

 Summary of the article:

Revisiting loxapine: a systematic review. Popovic D, Nuss P, Vieta E. Ann Gen Psychiatry. 2015 Apr 1;14:15. doi: 10.1186/s12991-015-0053-3

Do antipsychotics differ in weight gain during first episode treatment? Early Inter Psy.2015.Epub, June, 2015


Obesity contributes significantly to poor cardiac health among individuals with psychosis. Cardiovascular risk doubles in first year of treatment with antipsychotics.  Antipsychotics (AP) contribute heavily to this weight gain. Prevention of rapid weight gain during the early period of psychosis should be a major aim.

Meta analysis suggest that anti histaminic antipsychotics (clozapine, olanazapine, chlorpromazine, quetiapine) and 5HT2C blockers ( risperidone, paliperidone) are more likely to cause weight gain compared to pure D2 blockers like haloperidol. Contributing factors/ mechanisms involved in weight gain chronic schizophrenia while on AP may be different  from first episode cases.

Tel C et al conducted a meta-analysis of all AP studies in first- episode patients looking at weight changes during  short-term (≤12 weeks) and long-term (>12 weeks) treatment. Studies on first episode psychosis patients ( minimum age of 15, less than 16 weeks AP treatment in life time or AP naive at entry, treatment provided in OP settings) were included. Short term AP treatment was defined as less than 12 weeks, long term was defined as  13-52 weeks. Since there is no placebo controlled study in first episode patients, study sample with prodromal patients were used to calculate placebo controlled group outcomes.


From 3059 studies identifies initially, 28 studies that met all inclusion criteria were analysed.  Majority (22) of these were open label studies.

Mean weight gain difference was 3.22 kg in AP group compared to placebo.  The mean weight difference was significantly higher in Western countries (4.17 kg, CI = 3.38–4.96) than in Asian countries (1.36 kg, CI = −0.25 to 2.99).

Long term effect on weight : 5.30 kg  mean gain difference  between AP medications and placebo ( CI = 2.87–7.74, P < 0.001)

Olanzapine (n = 6, 9.34 kg (CI = 5.55– 13.12), P < 0.001) and clozapine (n = 2, 7.19 kg (CI = 0.28–14.09), P = 0.041) were the interventions associated with the highest weight gain compared to placebo. The only one intervention with perphenazine reported weight loss (−0.41 kg)

Ziprasidone maintains weight benefit effect in first episode samples. (This is already shown in chronic schizophrenia samples). This might be down to  noradrenaline re uptake blocking effects. Individual risk even with  Ziprasidone is not negligible. Ziprasidone registration studies showed that 7-16% participants gained significant weight. Olanzapine and  Clozapine consistently show increase in weight irrespective of stage of illness.

Haloperidol, unlike in studies of chronic schizophrenia patients, was associated with both short- and long-term weight gains in this analysis. Aripiprazole’s advantage shown in previous studies was not observed in this. Long term studies of aripiprazole on weight are lacking.

There seems to be no advantage in selecting Olanzapine as first or second agent in first episode patients, though studies still show that this medication continue to be  the commonly used antipsychotic.

Medication studies need to ensure that baseline weight, BMI and percentage increase  as well as dose -weight relationship are reported  routinely.

Comment: Weight gain need to be monitored closely and choice of AP should consider this effect. This is more so important during early stage of AP treatment.

Summary of article:

Antipsychotic-induced weight gain in first-episode psychosis patients: a meta-analysis of differential effects ofantipsychotic medications.

Tek C, Kucukgoncu S, Guloksuz S, Woods SW, Srihari VH, Annamalai A.

Early Interv Psychiatry. 2015 May 12. doi: 10.1111/eip.12251. [Epub ahead of print]

Is verbal abuse in childhood associated with earlier onset of bipolar disorder? Bipol Dis May 2015.


Childhood adversity is associated with an earlier age of onset of bipolar disorder. They also tend to show a more difficult course. Sexual and physical abuse are the main childhood adversities studied in this regard. Verbal abuse is more common, but  the role of verbal abuse in isolation  has not been studied.

Would verbal abuse in childhood lead to early onset of bipolar disorder? Do they have  a more difficult course?

Post RM et al studied whether history of isolated verbal abuse in childhood would impact the age of onset of bipolar disorder. They examined the self reported verbal abuse by 634 adult bipolar outpatients in 4 US clinics.The question for verbal abuse was “ have you ever experienced mistreatment such as intimidation, threats, humiliation, or verbal abuse that caused you serious emotional harm? ” with further questions to clarify frequency and age at which it occurred.


59% of the sample experienced verbal abuse in childhood ( along with other types of abuse) , with 24% reported having only verbal abuse in childhood.A significant effect was found for increased frequency of verbal abuse and earlier age of onset of bipolar disorder. Combination of sexual and verbal abuse lowered the age of onset of bipolar disorder ( as compared to  sexual abuse alone).The group with only verbal abuse (e.g., no physical or sexual abuse) showed significant increases in anxiety disorder comorbidity, drug abuse comorbidity, and rapid cycling, but not alcohol abuse.

Limitations: Subjective and retrospective data have the limitation that it is  subject to a variety of recall biases. However self reports are proven to be reliable methods in these contexts.

Comments: The association might be relevant to other psychiatric disorders as well. Relationship can be explained by psychological and biological mediating factors. For example, interpersonal violation ( =abuse) is associated with abnormalities in white matter tracts and size of hippocampus. Revising and restructuring   the childhood memories using psychotherapeutic techniques  is possible. This study also generate further understanding on what might help in preventing adult mental disorders.

Summary of the article

Verbal abuselike physical and sexual abuse, in childhood is associated with an earlier onset and more difficult course of bipolar disorder. Post RM, Altshuler LL, Kupka R, McElroy SL, Frye MA, Rowe M, Leverich GS, Grunze H, Suppes T, Keck PE Jr, Nolen WA.

Bipolar Disord. 2015 May;17(3):323-30.

Do childhood trauma lead to early detectable changes in BDNF and cytokines? Act Psy.May.2015

27 05 2015

Childhood trauma contribute enormously to mental health problems in the society. Understanding the brain /psychological mechanisms  mediating such effects are  crucial to help us develop interventions.  Low BDNF levels are associated with childhood trauma among adults with  mental disorders. It is also noted that trauma interact with BDNF val66 met polymorphism,  where met allele carriers  are at higher risk. Another pathway to consider is cytokines, where  trauma might be activating and maintaining  elevated levels of inflammatory cytokines.

Adults with a history of childhood trauma and psychiatric disorders show decrease in BDNF  and  increase in cytokines levels. A history of childhood trauma may set in changes in immune system functioning i.e.  leading to a permanent chronic inflammatory state . Lower BDNF expression in adulthood is related to poorer cognitive performance smaller hippocampal volumes , and increased psychiatric comorbidity . 

Do trauma lead to early detectable changes  in BDNF and cytokines?  Bucker J et al  report the results of a study asking this question.

Children who experienced  early trauma ( i.e.  trauma before age 4) were recruited from a foster home and child protection programme in South Brazil. They were between the ages of 3 and 12. A matching control group was also recruited. A structured interview identified psychiatric diagnosis (  in accordance with DSM-IV criteria (K-SADS-E)). Socio demographic variables as well  as trauma history were collected in detail. BDNF plasma levels were measured by ELISA. Concentration of plasma cytokines were determined by flow cytometry.

There were 36 children with trauma and 26 children without trauma. Both groups were comparable in age gender, IQ and education years. Trauma groups BMI was higher. Half of the children in trauma group  had been exposed to more than one type of trauma. 20% reported sexual abuse. 75% of trauma group had subsyndromal psychiatric symptoms.


Trauma group showed significant high levels of BDNF and TNF Alpha, when controlled for previous infection status. This is in contrast to the finding of lower BDNF in adults  who experienced child hood trauma. This may be a compensatory mechanism that is activated in response to trauma. It is  possible that it may reflect the resilience mechanims,  given that the children are away from traumatic environment and that they currently do to have any psychiatric diagnosis. To check whether being in a safer environment was the reason for higher BDNF, authors checked  the relationship between the ‘ time since trauma cessation’  and BDNF levels . No relationship was observed between these two.

The small sample size means that study lacks  statistical power  for subanalyses.  Absence of a specific instrument to quantify aspects such as the severity and intensity of trauma is another limitation.  The control group can be described as  ‘supernormal’  due to the fact that they included only children without psychiatric symptoms.


Trauma during childhood  sets in motion biological changes that are detectable early on. Observed changes indicate effect on neural plasticity and inflammation. Changes observed in children ( in case of BDNF) are different from that in adults. Further research is needed to see  why some of those exposed to trauma show better outcomes than others, and to determine  vulnerability/ safety ‘windows’  in relation to age of trauma.

Summary of the article:

Brain-derived neurotrophic factor and inflammatory markers in school-aged children with early trauma.

Bücker J, Fries GR, Kapczinski F, Post RM, Yatham LN, Vianna P, Bogo Chies JA, Gama CS, Magalhães PV, Aguiar BW, Pfaffenseller B, Kauer-Sant’Anna M. Acta Psychiatr Scand. 2015 May;131(5):360-8.