Bipolar disorder and "completed suicide"

"Suicide rates in BD [bipolar disorder] vary between studies but our analyses show that they are approximately 20-30-fold greater than in general population."

That rather sober sentence comes from the results of the systematic review published by Plans and colleagues [1] looking at "the existing literature of completed suicide in BD patients." As per the words 'completed suicide' this was a review article specifically focused on looking at studies examining the very final decision taken to end ones life and acting upon it. The authors did look at "suicide attempts and suicidal behaviour" during the course of their review but only in the context of completed suicide.

Then to the cold, objective science... over 60 articles met the authors inclusion criteria and allowed researchers to review "epidemiological data, genetic factors, risk factors and treatment of completed suicide in BD." Aside from the quite startling risk of completed suicide in relation to a diagnosis of bipolar disorder, authors were also able to note some important risk variables too: "early onset, family history of suicide among first-degree relatives, previous attempted suicides, comorbidities." Another important statement was also made pertinent to that 'treatment' analysis: "Lithium is the only treatment that has shown anti-suicide potential" in line with other observations (see here).

What's more to say? Well acknowledging that the paths towards suicide are various and numerous (see here) and, more often that not, influenced by both internal and external factors, the connection between bipolar disorder and suicide risk is cemented by the Plans review. I could talk about how bipolar disorder and other depression-related illnesses (yes, illnesses) are potentially *connected* to various other diagnostic labels (see here for example) and, within that context, may very well influence suicide risk there too (see here). But there's nothing particularly novel about such discussions.

The 'lithium' bit to the Plans paper is also important to reiterate, and how such medication is truly a life-saver for some. As with all medicines, it does have a 'risk profile' [2] but, with appropriate monitoring, any side-effects need to be balanced against the very real risk highlighted by Plans et al.

And then there is the need for lots more scientific investigation in this area to directly 'tackle' bipolar disorder in terms of aetiology and pathology and logically onward, to impact on suicide risk...

To close, there are people to talk to (or text) if needed...

----------

[1] Plans L. et al. Association between completed suicide and bipolar disorder: A systematic review of the literature. J Affect Disord. 2018 Aug 23;242:111-122.

[2] Albert U. et al. Lithium treatment and potential long-term side effects: a systematic review of the literature. Riv Psichiatr. 2014 Jan-Feb;49(1):12-21.

----------

"ADHD was a risk factor for suicide attempt"

The findings reported by Kai-Lin Huang and colleagues [1] continue an important research theme (see here) on how a diagnosis of attention-deficit hyperactivity disorder (ADHD) may increase the risk of suicidal behaviours (see here). Further, that timely management of the symptoms of ADHD via indicated pharmacological means in particular, may provide some important risk-reduction from such behaviours; again substantiating previous investigations in this area (see here).

Based, yet again, on the fabulous but now sadly non-functional resource that is/was the National Health Insurance Research Database (NHIRD) in Taiwan, researchers undertook a "longitudinal cohort study [that] enrolled 20 574 adolescents and young adults with ADHD and 61 722 age- and gender-matched controls between 2001 and 2009." This is yet another example of Taiwanese 'big data' in action on the important topic of suicide (see here and see here). Alongside detailing any psychiatric comorbidities accompanying the diagnosis of ADHD, Huang and colleagues looked for diagnostic codes indicating suicide attempt(s) and whether or not medication(s) clinically indicated for ADHD were prescribed.

Results: "ADHD was an independent and direct risk factor for any suicide attempt, and an even stronger risk factor for repeated suicide attempts." As per my previous blogging forays into this topic, such news is by no means novel. The use of "long-term methylphenidate treatment" being associated with "a significantly decreased risk of repeated suicide attempts in men with ADHD" is also not new news, but does once more, provide yet more evidence for the use of such strategies and their seeming effects well beyond just symptom reduction/management.

What's more to say? Well, one might need to delve a little more into what it is about ADHD that *might* predispose to such extremes of behaviour. Whether this be a heightened risk of other comorbidity occurring as a function of ADHD (see here) impacting on suicidal behaviour(s) or something rather more directly linked to ADHD (see here), there is a schedule of further research to continue. I'm also minded to direct your attention to the findings reported by Mars and colleagues [2] and how general population 'risk factors' might also provide some clues. Minus any medical or clinical advice given or intended, I'll reiterate how the use of something like lithium seems to be quite useful in the context of potentially reducing suicide risk (see here) and how further work perhaps needs to be done on this compound with specific focus on suicide risk and ADHD. I say this, bearing in mind that lithium has a risk profile of its own.

Oh, and need I remind you that ADHD as being an 'over-represented' feature of autism for quite a few people (see here) might also imply some 'association' in the very serious statistics talking about suicide risk in the context of autism (see here)...

Again, if anyone needs to talk to someone, there are organisations out there willing to listen.

----------

[1] Huang KL. et al. Risk of suicide attempts in adolescents and young adults with attention-deficit hyperactivity disorder: a nationwide longitudinal study. Br J Psychiatry. 2018 Mar 4:1-5.

[2] Mars B. et al. What distinguishes adolescents with suicidal thoughts from those who have attempted suicide? A population-based birth cohort study. J Child Psychol Psychiatry. 2018 Mar 1.

----------

Chronic kidney disease is over-represented in cases of serious mental illness

The findings reported by Masao Iwagami and colleagues [1] observing that "CKD [chronic kidney disease] is identified more commonly among patients with SMI [serious mental illness] than in the general population" are not entirely novel. I've touched upon this topic before (see here), set within the broader perspective that physical / somatic ailments experienced by those with a psychiatric and/or behavioural diagnosis can sometimes be 'downplayed' in light of their receipt of a 'primary' psychiatric / behavioural label. It stretches across various different labels (see here for example) with sometimes catastrophic outcomes.

Iwagami et al started out with the premise that risk factors for CKD - "a long-term condition where the kidneys don't work as well as they should" - including tobacco smoking and diabetes, are more frequently reported in those diagnosed with an SMI, hence their risk of CKD may be greater. To see if there was any heightened association between SMI and CKD here in Blighty, they relied on data from a resource called the Clinical Practice Research Datalink (CPRD). CPRD allows researchers to access various details from patient records based on the accrual of primary healthcare data. Importantly, as well as containing read codes for SMI, the database also includes laboratory test results pertinent to CKD: "CKD was based on two measurements of estimated glomerular filtration rate <60 mL/min/1.73 m2 separated by 3 months or longer; calculated from serum creatinine." The combined data was analysed and 'adjusted' for various potentially confounding variables including lithium use (lithium can affect kidney function).

From a starting population of some 2.5 million people (records), authors identified a diagnosis of SMI in about 28,000 (~1%). Most of those 28,000 or so diagnosed with a SMI had no history of lithium use (24,101 / 28,396). The prevalence of CKD was 14.6% in those with a SMI and history of lithium use. The prevalence of CKD was 3.3% in those with a SMI and no history of lithium use. This compares with a CKD prevalence rate of 2.1% in the population not diagnosed with a SMI (N=2,387,988). Ergo: "patients with SMI had a greater prevalence of CKD compared to the general population." Authors also mention how risk of renal replacement therapy (RRT) was also increased in those with a SMI.

This is important data. It's not foolproof data insofar as "a greater prevalence of CKD among patients with SMI may, in part, be influenced by surveillance or ascertainment bias. Patients with SMI take medications, such as lithium and other psychotropic drugs, which need regular monitoring." It does however suggest that regular screening for CKD needs to be a priority for those diagnosed with a SMI particularly given that "CKD is strongly and independently associated with mortality and cardiovascular risk" (something else mentioned in the context of certain psychiatric diagnoses). But there is also something rather uncomfortable in the Iwagami results: that possibility of an advanced risk of CKD in cases of SMI with a history of lithium use.

Minus any clinical or medical advice given or intended on this blog, I can see why the authors haven't overplayed the potential effect of lithium use on their results. Lithium, in the context of various psychiatric disorders and beyond, is an important medication, particularly when it comes to its proposed properties as an 'anti-suicidal' agent (see here). It really does save lives. But as with just about every medicine available, there is an important cost-benefit ratio to take into account when prescribing this medication and ensuring regular monitoring is available to minimise any side-effects. I might also add that there are *possibilities* [2] when it comes to potentially reducing some of the effects that lithium use might have on kidney function but I'll leave such discussions to the experts.

For now, we have further evidence that for whatever reason(s), being diagnosed with a SMI has the potential to impact on many areas of health, both mental and physical.

----------

[1] Iwagami M. et al. Severe mental illness and chronic kidney disease: a cross-sectional study in the United Kingdom. Clin Epidemiol. 2018 Apr 16;10:421-429.

[2] Lodin M. & Dwyer J. The role of amiloride in managing patients with lithium‐induced nephrogenic diabetes insipidus. J Pharmacy Practice & Research. 2017; 47(5): 389-392.

----------

"evidence to date is overwhelmingly in favour of lithium as an antisuicidal agent"

If the systematic review and/or meta-analysis sits at the top of the evidence-based pyramid then a systematic review of existing systematic reviews in a particular area should perhaps be the cherry on the top.

The paper published by Katharine Smith & Andrea Cipriani [1] is that cherry on top of the pyramid, looking at a topic of some interest to some of this authorship group [2] on how the "evidence to date is overwhelmingly in favour of lithium as an antisuicidal agent."

I've talked about lithium a few times on this blog (see here and see here) including research pertinent to the idea that the lithium content of public drinking water supplies might show an interesting *relationship* with suicide rates roundabout (see here). Such work stemming from the idea that lithium might have some rather important (positive) influences on suicide prevention [3] for whatever reason(s).

Smith & Cipriani searched the peer-reviewed literature for "systematic reviews and meta-analyses of RCTs [randomised controlled trials] of lithium and suicide and self harm." They found a handful of papers meeting their guidance and with them 'overwhelming' evidence that lithium does seem to impact on risk of suicide. They comment on the fact that there is more to do in this area; for example on: "the supporting evidence that observational and non-randomized studies can also provide" but present an important case that lithium use "should be incorporated more assertively into current guidelines" when it comes to suicide prevention.

Bearing in mind the cost-benefit profile of lithium [4] and that suicide - whether ideation, attempt or completion - stems from a complicated (and often individual) set of circumstances, this is one area where the term 'life-saving' is not to be under-emphasised. And I can think of at least one label where quite a bit more 'life-saving' is required (see here)...

----------

[1] Smith KA. & Cipriani A. Lithium and suicide in mood disorders: Updated meta-review of the scientific literature. Bipolar Disord. 2017 Sep 12.

[2] Cipriani A. et al. Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis. Database of Abstracts of Reviews of Effects (DARE). 2013.

[3] Lewitzka U. et al. The suicide prevention effect of lithium: more than 20 years of evidence—a narrative review. International Journal of Bipolar Disorders. 2015;3:15.

[4] Albert U. et al. Lithium treatment and potential long-term side effects: a systematic review of the literature. Riv Psichiatr. 2014 Jan-Feb;49(1):12-21.

----------

On drinking water lithium content and dementia risk

"Lithium in tap water may cut dementia" went the BBC website headline reporting the study results published by Lars Vedel Kessing and colleagues [1]. The authors relied on some of those oh-so important Scandinavian population registries and other data to examine a possible connection between drinking water lithium levels and risk of "diagnosis of dementia in a hospital inpatient or outpatient contact."

Alongside looking at data for some 70,000 people diagnosed with dementia and nearly three-quarters of a million non-diagnosed controls, researchers estimated lithium exposure via drinking water based on data from over 150 waterworks. The relationship they observed between lithium in drinking water and risk of dementia diagnosis was not altogether straight-forward as "higher long-term lithium exposure from drinking water may be associated with a lower incidence of dementia" but the relationship was described as "nonlinear." Nonlinear meant that those with drinking water levels of lithium at moderate levels - between 5.1 and 10 micrograms per litre - actually showed an increased risk of dementia compared to those who had low levels of lithium (below 5 micrograms per litre) in their drinking water. The authors add: "Nonlinear dose-response associations are often found in medicine, with a gradual increase in drug response at the lower doses and gradual leveling off in response at the highest doses."

The authors do caution about their results and the various limitations attached to the findings. Not least is their reliance on a diagnosis of dementia as a starting point and how factors such as "accessibility to health care services that vary geographically" may have influenced such results. Indeed they note: "accessibility to health care services is increased in eastern regions of Denmark, where lithium levels generally are higher, and decreased in western regions, specifically in Jutland, where lithium levels generally are lower." They also found: "a direct inverse association with increasing risk of dementia in rural areas" as part of a sensitivity analysis, and as noted in some other studies [2]. More investigation is definitely required.

But these remain interesting results. Lithium is a treatment of choice when it comes to conditions such as bipolar disorder (see here). I've also talked about this stuff in connection to some other important research looking at suicide reduction too (see here) based on quite a body of research [3] (and growing all the time [4]) but minus simplifying something like suicide ideation, attempts or completion all down to lithium 'deficiency'. In relation to the possible effects on dementia risk, this is not the first time that lithium has been discussed as per findings looking at dementia risk in cases of lithium treated bipolar disorder [5] (something else that has been discussed on this blog - see here).

Questions still however remain. The mechanism of effect(s) is still to be suitably deciphered and one also needs to keep in mind the safety profile of lithium [6] as a balance to any risk-reduction effects on dementia or anything else. This is particularly relevant to those who might be at particular risk for dementia [7]. I'll also add that any focus on lithium intake and dementia also needs to keep in mind other *associations* that have been previously discussed in the peer-reviewed research literature such as that talking about vitamin D deficiency and dementia risk for example (see here) as part of a wider research interest in vitamin D and cognitive functions in the context of ageing (see here).

----------

[1] Kessing LV. et al. Association of Lithium in Drinking Water With the Incidence of Dementia. JAMA Psychiatry. 2017 Aug 23.

[2] Contador I. et al. Childhood and Adulthood Rural Residence Increases the Risk of Dementia: NEDICES Study. Curr Alzheimer Res. 2015;12(4):350-7.

[3] Cipriani A. et al. Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis. BMJ. 2013 Jun 27;346:f3646.

[4] Kanehisa M. et al. Serum lithium levels and suicide attempts: a case-controlled comparison in lithium therapy-naive individuals. Psychopharmacology (Berl). 2017 Aug 28.

[5] Gerhard T. et al. Lithium treatment and risk for dementia in adults with bipolar disorder: population-based cohort study. Br J Psychiatry. 2015 Jul;207(1):46-51.

[6] Albert U. et al. Lithium treatment and potential long-term side effects: a systematic review of the literature. Riv Psichiatr. 2014 Jan-Feb;49(1):12-21.

[7] Holroyd S. & Rabins PV. A Retrospective Chart Review of Lithium Side Effects in a Geriatric Outpatient Population. Am J Geriatr Psychiatry. 1994 Autumn;2(4):346-351.

----------

The autisms, case reports and two 'intervention' options

I'm looking at two papers today which I'd like to think cover the title of this post pretty well dealing with the plurality of autism - the autisms - and the idea that intervention or management-wise, there is no 'one size fits all' when it comes to the autisms.

First up are the findings reported by Ziats and colleagues [1] who presented results for a child - "A 4-year-old male with autism and two episodes of neurodevelopmental regression" - who was also found to have a "mutation in the TMLHE gene, which encodes the first enzyme in the carnitine biosynthesis pathway, and concurrent carnitine deficiency." Supplementation with carnitine (see here) seemed to lead to some interesting changes in the developmental profile for this boy such that: "the patient's regression ended, and the boy started gaining developmental milestones."

Accepting that this was another example of the N=1 and autism (see here) I was rather interested in these results having previously blogged about issues with the TMLHE (trimethyllysine hydroxylase) gene in relation to autism (see here). The source of that previous post was the paper from Patricia Celestino-Soper and colleagues [2] (open-access) who concluded that: "TMLHE deficiency is a risk factor for autism" and quite a bit more should be done to screen for such issues. I wouldn't disagree with those sentiments (see here).

Next up are the results reported by Serret and colleagues [3] (open-access) who presented findings based on two participants "diagnosed with autism spectrum disorders in childhood and presented regression with catatonia features and behavioural disorders after a stressful event during adolescence." Further: "both patients presented mutation/microdeletion of the SHANK3 gene, inducing a premature stop codon in exon 21." Issues with SHANK3 have been reported in relation to autism previously.

Authors reported that: "lithium therapy reversed clinical regression, stabilized behavioural symptoms and allowed patients to recover their pre-catatonia level of functioning, without significant side effects." Further: "These cases support the hypothesis of a specific SHANK3 phenotype" and that lithium might hold some favour in improving clinical presentation in those cases.

Again, I was interested in the Serret findings with the caveat about their also using the case study approach in their paper. Lithium is an interesting compound that has graced this blog a few times in relation to its potential 'anti-suicide' correlating properties (see here) and as a possible management tool when it comes to the presentation of mood disorders comorbid to a diagnosis of autism (see here). Accepting that lithium has its own potential side-effects profile, the idea that cost-benefits might be calculated and if so deemed more benefit and less cost subsequently applied to 'some' autism, is an interesting prospect.

Reiterating my opening paragraph, what the Ziats and Serret papers serve to tell us is that within 'the autisms' there may be many different roads to a diagnosis of autism and that under the diagnostic label of 'autism', genetics, biochemistry and subsequent intervention/management strategies may vary from person to person. As I've said before, receipt of a diagnosis of autism (when it is eventually received) should be a starting point for further inquiry not the 'finishing line'.

That comorbidity - if I can still call it that - might also be a 'target' for analysis and investigation is also an important point raised and further asks more questions about the value of intervening on said comorbidity and the possible knock-on effects on the presentation of more core autism symptoms (see here). Y'know something like what is emerging in the body of research looking at anxiety and autism (see here).

With the body of work linking this, that and t'other to autism I'm starting to think that some further resources might be needed to pull all the available peer-reviewed information together in terms of what factors have been linked to those 'autisms'. I've always been very partial to autism research looking at inborn errors of metabolism (IEMs) as a starting point for investigations (see here) given both the data on overlap and even the idea that some of the various interventions for specific IEMs might hold promise for 'some' autism (see here). Analysis of things like rare genetic variations also being linked to the appearance of autism (see here) ties into the IEM investigations and perhaps represents the next tier of evaluation, bearing in mind the reduced costs of things like whole genome sequencing these days set within the perspective of personalised medicine (see here). Environment, bearing in mind the range of factors this might cover, should also be included in any diagnostic work-up based on the evolving science connecting something like infection to autism onset for some (see here and see here). There are various tests that could be performed covering a whole slew of potential infective agents (see here).

This is just a rough-and-ready idea of where autism research and practice could go with this but much like the pathways to diagnosing and managing bowel issues when comorbid to autism for example (see here), a general diagnostic roadmap is perhaps indicated...

Music: Years & Years - King.

----------

[1] Ziats MN. et al. Improvement of regressive autism symptoms in a child with TMLHE deficiency following carnitine supplementation. Am J Med Genet A. 2015 May 5.

[2] Celestino-Soper PB. et al. A common X-linked inborn error of carnitine biosynthesis may be a risk factor for nondysmorphic autism. Proc Natl Acad Sci U S A. 2012 May 22;109(21):7974-81.

[3] Serret S. et al. Lithium as a rescue therapy for regression and catatonia features in two SHANK3 patients with autism spectrum disorder: case reports. BMC Psychiatry 2015, 15:107.

----------

Ziats MN, Comeaux MS, Yang Y, Scaglia F, Elsea SH, Sun Q, Beaudet AL, & Schaaf CP (2015). Improvement of regressive autism symptoms in a child with TMLHE deficiency following carnitine supplementation. American journal of medical genetics. Part A PMID: 25943046




Serret, S., Thümmler, S., Dor, E., Vesperini, S., Santos, A., & Askenazy, F. (2015). Lithium as a rescue therapy for regression and catatonia features in two SHANK3 patients with autism spectrum disorder: case reports BMC Psychiatry, 15 (1) DOI: 10.1186/s12888-015-0490-1

Uric acid and bipolar disorder

Bipolar disorder appearing again on this blog this week? It's just the way that the papers fall...

With a title like: 'Increased uric acid levels in bipolar disorder subjects during different phases of illness' I was hardly likely to pass up the opportunity to discuss the paper by Umberto Albert and colleagues [1] and their suggestion that there may be a lot more to see when it comes to "a purinergic dysfunction associated with BD [bipolar disorder]".

I lost the defuser gun when I misplaced the invisible car.

Based on the analysis of serum uric acid (UA) levels in 150 participants formally diagnosed with BD compared with "150 age- and gender-matched subjects with MDD [major depressive disorder], OCD [obsessive compulsive disorder], or Schizophrenia", researchers reported that: "Mean serum UA levels (5.06±1.45 vs. 4.17±1.05mg/dL) and rates of hyperuricaemia (30.7% vs. 6.7%) were significantly higher in the bipolar than in the control group." The authors pointed out the limitations of their study: "Our study suffers from the lack of a healthy comparison group; moreover, longitudinal data are missing" so no need for me to say anything further in that respect.

Uric acid, more commonly associated with a condition like gout, has been getting quite a bit of research attention when it comes to behaviour and psychiatry down the years. I've talked previously on this blog about the intriguing work suggestive of a possible connection between levels of uric acid and impulsivity (see here) highlighting a possible biology - trait connection. As per the Albert findings - "No differences were detected between bipolars in different phases of illness, with all three groups (manic, depressive and euthymic bipolars) showing significantly higher UA levels as compared to controls" - other research has hinted that the relationship between uric acid and BD is quite a bit more than just one related to trait [2]. I'm open to accepting that this might however change as more research is done on this topic.

Mechanism of effect for uric acid in BD? A very good question. Unfortunately I don't have a good answer at the moment, aside from reiterating the Albert suggestion "of a purinergic dysfunction associated with BD". Going all the way back to the 1921 book by Emil Kraeplin where the connection between uric acid and "manic symptoms" was discussed, there is quite a long history attached to this area. Even further back, the paper by Sutherland (1892) [3] talked about uric acid diathesis in children exemplified by: "keen precocious minds, and small restless bodies; they are excitable, nervous, bright and amusing at one time, and greatly depressed at another". Lithium salts were the treatment of choice for the 'gouty diseases' [4] and perhaps might offer some further explanation for the mechanism of effect in BD.

Other than that I can say no more, aside from pointing out that if one considers uric acid to be an agent of inflammation [5] and associated with other inflammatory responses [6], one might entertain some possible association between elevated levels of the stuff and other potentially important work in the area of BD...

And to close: White Coats by Foxes.

----------

[1] Albert U. et al. Increased uric acid levels in bipolar disorder subjects during different phases of illness. J Affect Disord. 2014 Nov 15;173C:170-175.

[2] Kesebir S. et al. Increased uric acid levels in bipolar disorder: is it trait or state? J Biol Regul Homeost Agents. 2013 Oct-Dec;27(4):981-8.

[3] Sutherland GA. On some Symptoms Associated with the Uric Acid Diathesis in Children. Br Med J. 1892 Apr 23;1(1634):856-8.

[4] Amdisen A. & Hildebrandt J. Use of lithium in the medically ill. Psychother Psychosom. 1988;49(2):103-19.

[5] Shi Y. Caught red-handed: uric acid is an agent of inflammation. The Journal of Clinical Investigation 2010;120(6):1809-1811. doi:10.1172/JCI43132.

[6] Lyngdoh T. et al. Elevated serum uric acid is associated with high circulating inflammatory cytokines in the population-based Colaus study. PLoS One. 2011;6(5):e19901.

----------

Albert U, De Cori D, Aguglia A, Barbaro F, Bogetto F, & Maina G (2014). Increased uric acid levels in bipolar disorder subjects during different phases of illness. Journal of affective disorders, 173C, 170-175 PMID: 25462413

Lithium for mood disorder symptoms in autism?

Modern classroom? @ Wikipedia 

The paper published by Matthew Siegel and colleagues [1] talking about some preliminary observations on the use of lithium where symptoms of mood disorder might be present in cases of autism spectrum disorder (ASD) caught my eye recently. Concluding that: "lithium may be a medication of interest for those who exhibit two or more mood disorder symptoms, particularly mania or euphoria/elevated mood" the sentiments of more research-to-do in this area presents some intriguing options. That all being said, side-effects of lithium supplementation may yet scupper any large-scale plans for using this medication option with this cohort as per the authors note that: "Forty-seven percent of patients were reported to have at least one side effect, most commonly vomiting (13%), tremor (10%), fatigue (10%), irritability (7%), and enuresis (7%)".

I had a few thoughts after reading the Siegel paper and their findings based on the use of Clinical Global Impressions - Improvement (CGI-I) ratings that "Forty-three percent of patients who received lithium were rated as "improved"". Mood disorders, or the symptoms of mood disorders, covers quite a bit of diagnostic ground. My recent discussions on bipolar disorder being fairly frequent in cases of Asperger syndrome (see here) coincide with the Siegel findings and particularly the case report by Frazier and colleagues [2] discussing a treatment regime which mentions the use of lithium. Other reports have similarly described the use of lithium as a possible management option where bipolar disorder and autism are comorbid [3]. What this tells me is that Siegel et al were not the first to look at lithium and autism (with comorbidity).

A quick glance at the other peer-reviewed literature in this area suggests that lithium is also finding some favour where less idiopathic types of autism are present. The paper by Luiz & Smith [4] talking about lithium as a promising treatment for Fragile X syndrome represents another potentially important area. The precise mode of action is still the subject of some conjecture but the overview provided by Chiu & Chuang [5] (open-access) gives some indication of what might be going on and could be similarly mapped on to potential biological mechanisms linked to autism and mood disorder if and when comorbid.

Finally, I have to make some mention about the important links being made between the use of lithium and the prevention of suicide in mood disorders [6]. I know it's not exactly a topic which makes great dinner party conversation but the emerging evidence base, alongside other important compounds, could potentially be life-saving for some people. Without trying to brush everyone on the autism spectrum as being at risk from suicide, the growing body of evidence suggesting that suicide ideation (see here) or suicide attempts (see here) might be more frequent for those on the autism spectrum [7] is something that needs to be taken seriously. This may imply that alongside appropriate societal support being provided, lithium might also have some important role to fulfil for some people...

----------

[1] Siegel M. et al. Preliminary Investigation of Lithium for Mood Disorder Symptoms in Children and Adolescents with Autism Spectrum Disorder. J Child Adolesc Psychopharmacol. 2014 August 5.

[2] Frazier JA. et al. Treating a child with Asperger's disorder and comorbid bipolar disorder. Am J Psychiatry. 2002 Jan;159(1):13-21

[3] Kerbeshian J. et al. Lithium carbonate in the treatment of two patients with infantile autism and atypical bipolar symptomatology. J Clin Psychopharmacol. 1987 Dec;7(6):401-5.

[4] Liu Z. & Smith CB. Lithium: A Promising Treatment for Fragile X Syndrome. ACS Chem Neurosci. 2014 May 15.

[5] Chiu CT. & Chuang DM. Molecular actions and therapeutic potential of lithium in preclinical and clinical studies of CNS disorders. Pharmacol Ther. 2010 Nov;128(2):281-304.

[6] Cipriani A. et al. Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis. BMJ. 2013 Jun 27;346:f3646.

[7] Paquette-Smith M. et al. History of Suicide Attempts in Adults With Asperger Syndrome. Crisis. 2014; 35: 273-277.

----------

Siegel M, Beresford CA, Bunker M, Verdi M, Vishnevetsky D, Karlsson C, Teer O, Stedman A, & Smith KA (2014). Preliminary Investigation of Lithium for Mood Disorder Symptoms in Children and Adolescents with Autism Spectrum Disorder. Journal of child and adolescent psychopharmacology PMID: 25093602

Increased rates of suicidal ideation in adults with Asperger syndrome

"Our findings lend support to anecdotal reports of increased rates of suicidal ideation in adults with Asperger's syndrome, and depression as an important potential risk factor for suicidality in adults with this condition".

Sunrise @ Wikipedia 

That was the very stark conclusion reached by the study by Sarah Cassidy and colleagues [1] (open-access) looking at self-reported rates of suicide ideation and suicide plans/attempts in a sample of adults newly diagnosed with Asperger syndrome attending a "specialist diagnostic clinic" between 2004 and 2013. That depression seemed to play an important role in the engagement of such extreme thoughts or behaviour was also important. The press release accompanying the research can be read here.

As per some previous discussion on this topic (see here), suicide, whether attempted or completed, is a difficult topic to talk about. Not only because of the emotions which it invariably stirs up but also because the various paths towards someone reaching such an extreme point are complex, often very individual and still not well understood. Among the various risk factors suggested to be linked to [completed] suicide [2] some key points quite consistently come out including (a) a previous history of suicide ideation or suicide attempts, (b) the presence of psychiatric comorbidity such as depression or psychotic illness, and (c) some degree of social exclusion or alienation. I should mention that this is not an extensive list of risk factors, merely those which seem to appear with greatest frequency in the various research literature in this area.

The Cassidy paper is open-access but a few points are pertinent:

• As part of their attendance at clinic, nearly 400 adults ranging in ages from 17 - 67 years old at time of diagnosis, completed a self-report "patient screening questionnaire" containing items of about suicide and mood. The paper states the relevant questions: "have you ever been diagnosed with depression?", "have you ever felt suicidal?" and "if yes, have you ever planned or attempted suicide?".
• Participant were also asked to complete the Empathy Quotient (EQ) and the Autism Spectrum Quotient (AQ) questionnaires, both self-report measures which provide information about empathy and some of the "cognitive-behavioural traits associated with autism". Data derived from the suicide questioning items were compared with "published rates of suicidal ideation in the general population and other clinical groups".
• Results: "a 66% lifetime experience of suicidal ideation and a 35% lifetime experience of planned or attempted suicide supports the assertion that these occurrences are common in people with Asperger's syndrome". Compared with the population control data on these issues, the authors report that their sample were "more likely to report lifetime experience of suicidal ideation than were individuals from a general UK population sample". This included those with medical illnesses or psychotic illness. But... those with drug dependency and ADHD were still marginally more likely to report suicide ideation.
• Depression also seemed to play it's part in the reports. "Individuals with a history of depression ... were more likely to report suicide ideation ... and more likely to report suicide plans or attempts" compared with those without depression. And as for the EQ and AQ data, well higher scores on the AQ seemed to link with those reporting suicide plans or attempts but that was about it.

There are limitations to this study based on issues like the use of self-report questionnaire items asking about things like planned or attempted suicide or depression diagnosis without other evidence sources. Also as the authors note, their focus on "the population of people who reach adulthood without a diagnosis of Asperger's syndrome" is relevant. But the results are pretty stark particularly in respect to the numbers who have actually planned or attempted suicide. 

Going back to those more generalised population risk factors linked to suicide ideation or completion, it's not difficult to see how many of those might especially apply to some diagnosed with Asperger syndrome. Comorbidity such as depression is quite a well-known issue in relation to the autism spectrum [3]. Indeed, not so long ago I was interested to read the paper by Gotham and colleagues [4] on how rumination - "compulsively focused attention on the symptoms of one's distress" - might play a role in depression in some cases of autism and where this could lead from a therapeutic standpoint. I'll also direct you to the paper by Ljung and colleagues [5] concluding that: "Attention-deficit/hyperactivity disorder [ADHD] is associated with an increased risk of both attempted and completed suicide" which might tie into the links being made between autism and ADHD (see here).

Insofar as other conditions more generally linked to suicide such as psychosis [6] there is also perhaps something to do with the Cassidy results in mind, as a consequence of Asperger syndrome not being protective against the development of psychosis (see here). Social exclusion or alienation is also something reported with regards to the autism spectrum. I'm due to publish a mega-post quite soon on some of the research literature looking at quality of life (QoL) with autism in mind. Certainly in amongst that collected work, there are multiple examples of how loneliness and social isolation can be very detrimental factors to QoL.

At this point I'm also minded to bring in the possibility that suicide ideation or planning might not be just solely due to psychological or societal factors but rather may be influenced by something like biology too. Regular readers of this blog probably already know about my fascination with all-things vitamin D. It's timely that I talked about some of the collected literature looking at vitamin D deficiency in relation to something like depression recently (see here). Even perhaps more timely that said deficiency of the sunshine vitamin/hormone might also be something to look at with [adult] autism in mind (see here). I'm not necessarily suggesting a cause-and-effect scenario linking these elements, merely that this could be something to look at in future. Perhaps also in the same light as looking at another interest of mine: gluten and "feelings of depression"? How about other trace minerals and suicide too?

Whatever the reasons for thoughts of suicide to be linked to the autism spectrum, there is an important message to come from the Cassidy results and other papers on this topic: "inform appropriate service planning and support to reduce risk in this clinical group". Or I could just say make greater efforts to ensure that everyone knows how valuable their lives are, how valued they are as individuals and that there are people to talk to...

Everybody Hurts... so hold on.

----------

[1] Cassidy S. et al. Suicidal ideation and suicide plans or attempts in adults with Asperger's syndrome attending a specialist diagnostic clinic: a clinical cohort study. Lancet Psychiatry. 2014. June 25.

[2] Pelkonen M. & Marttunen M. Child and adolescent suicide: epidemiology, risk factors, and approaches to prevention. Paediatr Drugs. 2003;5(4):243-65.

[3] Matson JL. & Williams LW. Depression and mood disorders among persons with Autism Spectrum Disorders. Res Dev Disabil. 2014 Sep;35(9):2003-2007.

[4] Gotham K. et al. Rumination and Perceived Impairment Associated With Depressive Symptoms in a Verbal Adolescent-Adult ASD Sample. Autism Res. 2014 Jun;7(3):381-91.

[5] Ljung T. et al. Common Etiological Factors of Attention-Deficit/Hyperactivity Disorder and Suicidal Behavior. JAMA Psychiatry. 2014. June 25.

[6] Björkenstam C. et al. Suicide in first episode psychosis: A nationwide cohort study. Schizophr Res. 2014 May 31. pii: S0920-9964(14)00240-0.

----------

Sarah Cassidy, Paul Bradley, Janine Robinson, Carrie Allison, Meghan McHugh, & Simon Baron-Cohen (2014). Suicidal ideation and suicide plans or attempts in adults with Asperger's syndrome attending a specialist diagnostic clinic: a clinical cohort study Lancet Psychiatry : doi:10.1016/S0140-6736(08)61345-8

Suicide, vitamins and trace minerals

I'm straying a little bit with this post. Straying from the intended autism research blogging path but hopefully not too far beyond my competence as I offer some discussion on yet another very complicated and very emotive topic: suicide.

It's not that I haven't made mention of suicide on this blog before; quite a few times in fact, in relation to issues like poisoning by pesticide as being an important method of suicide which perhaps need further regulation (see here) and how a familiar name to this blog, Toxoplasma gondii (or T.gondii to those who know it well) might very well show some relationship to some cases of suicide (see here).

One previous post in particular on cholesterol levels and autism (see here) may also be of some relevance to half of this post, focused on some potentially important findings from John Umhau and colleagues* (open-access) on vitamin D levels and their potential connection to suicide among active service military personnel. My very limited knowledge of cholesterol and vitamin D stems from articles like this one which might in turn partially explain headlines like: Vitamin D Supplements Won't Help Cholesterol Levels. That being said, I'm not an expert.

The Umhau findings are of great interest, not only because military personnel represent a 'captive audience' (if you'll pardon the pun) in terms of availability for study and the information that can be collected - see my post on schizophrenia and milk here if you don't believe me - but also because this was a study where archived serum samples had already been collected from both those who went on to commit suicide (n=495) and those used as control participants (n=495) in the study.

It wasn't as simple as saying the group mean level of vitamin D - sorry, 25-hydroxyvitamin D [25(OH)D] - calcidiol (the prehormone, as opposed to calcitriol, the active form of vitamin D) were lower in all suicide cases, given that suicide is not just a biochemical process. No, but when various factors such as season of serum collection, any history of depression and ethnicity were controlled for, there was "a statistically significant association between 25(OH)D concentrations and suicide risk, such that subjects with higher concentrations of 25(OH)D displayed a decreased risk for suicide compared to subjects in the lowest octile". The authors add: "We found that the risk for suicide was increased in the lowest octile of 25(OH)D levels, all the members of which had seasonally adjusted levels of 25(OH)D below 20 ng/mL". One perhaps has to bear in mind that active service when it comes to military employment and deployment can bring about its own set of very special circumstances.

Another paper also cropped up fairly recently adding to the possibility of a biochemical factor potentially being related to suicide. Victor Blüml and colleagues** reported again, some interesting findings on how lithium in the water supply might be potentially related to suicide rates in the US State of Texas; to quote: "The findings provide confirmatory evidence that higher lithium levels in the public drinking water are associated with lower suicide rates". I'm not going to go too far into the hows and whys of this paper for a couple of reasons: (a) I don't yet have the full-text version of the paper so am solely reliant on what the abstract says, and (b) there are many others far more competent than I who have talked about lithium and psychiatry before; one of them being Dr Emily Deans and a post she wrote in January 2012 about lithium which offers much more information than I could. All I could add as a sort of peripheral factoid is reference to a paper by Singh and colleagues*** which suggested that lithium might not be the only target compound of future interest bearing in mind its safety profile.

Suicide is not just a biochemical process and neither is it a uniform process with I assume, lots of different factors converging to influence the steps a person takes before reaching such an ultimate decision to take their own life. The studies highlighted in this post offer some interesting correlates related to suicide which at best suggest we should be looking at environment - the physical environment - as a potential player in how some people reach such a point, but not simply to replace the multitude of other important variables which might come into play.

Just in case anyone in the UK needs to talk to someone, the Samaritans are always good listeners (most other countries have similar services).

----------

* Umhau JC. et al. Low vitamin d status and suicide: a case-control study of active duty military service members. PLoS One. 2013; 8: e51543.

** Blüml V. et al. Lithium in the public water supply and suicide mortality in Texas. J Psychiatr Res. January 2013.

*** Singh N. et al. A safe lithium mimetic for bipolar disorder. Nature Comms. 2013; 4.

----------

Umhau JC, George DT, Heaney RP, Lewis MD, Ursano RJ, Heilig M, Hibbeln JR, & Schwandt ML (2013). Low vitamin d status and suicide: a case-control study of active duty military service members. PloS one, 8 (1) PMID: 23308099