Depression

Recent Papers on Depression
1. Inflammatory behaviour
There is increasing evidence that chronic inflammation may alter mood and impact on the development of depression.
Patients with depression have higher levels of inflammatory cytokines and acute-phase proteins. Admin of stimulators of inflammation has been associated with symptoms of depression.
It has been shown that cytokines are involved in many pathways known to be central to depression mechanisms such as production of monamines, neuroendocrine function and various other mechanisms of mood regulation.
Various drug targets have been identified that may be useful in the treatment of the depressed and inflamed patient. These targets include various factors involved in the cyclooxygenase and MAP kinase pathways, and NF-κB, various cytokines and chemokines.
Factors contributing to a pro-inflammatory state such as stress, poor diet, obesity, a leaky gut, a T-cell imbalance in favour of inflammation could be relevant to depression and relapse and could be targets for treatment.
Identifying mechanisms by which pro- and anti-inflammatory cytokines might influence mood could in the future lead to personalized treatments to the depressed patient with an inflammatory component to their illness.
Haroon et al. Neuropsychopharmacol 2011 Sep 14. doi: 10.1038/npp.2011.205. [Epub ahead of print].
PMID: 21918508 [PubMed – as supplied by publisher]

2. Drugs for Geriatric Mood Disorders
Few new drugs have been developed to treat the major mood disorders, bipolar and depression.
In the treatment of the elderly depressed patient, the aim is to develop newer strategies with higher remission. They include combining antidepressants, mood stabilizers and psychotherapy to treat specific symptom clusters. One example is the additional treatment of cognitive impairment symptoms with cholinesterase inhibitors.
The use of genetic information to predict drug treatment outcomes has recently been investigated.
In the future, more individualized treatment combinations may improve outcomes and result in less adverse effects.
Diniz BS, Nunes PV, Machado Viera R, et al. Curr Opin Psychiatry 2011 Sep 13. [Epub ahead of print]
PMID: 21918446 [PubMed – as supplied by publisher]

3. Positive Mum Helps the Depressed Teenager
How parents express their emotions during interactions with their teenagers impact greatly on their children’s mood and their life adjustments. In this study, it was investigated to see if symptoms of depression in teenagers were associated with neural activity during exposure to their mothers’ behaviour.
A functional MRI of the brains of 30 adolescents (18 females, mean age 17) participated in a task that used video clips of their own mother’s and an unrelated mother affective behavior as stimuli. Adolescents with symptoms of depression showed reduced rostral cingulated activity during exposure to their own mother’s behaviour and reduced striatal activity during exposure to positive behavior in general.
In the light of this study and other evidence, it may be that there may be a deficit in the reward function during depression.
Adolescents’ depressive symptoms moderate neural responses to their mothers’ positive behavior.
Whittle S, Yücel M, Forbes EE, et al. Soc Cogn Affect Neurosci. 2011Sep 14. [Epub ahead of print]
PMID: 21917846 [PubMed – as supplied by publisher]

4. Endocannabinoids and mood
There is increasing evidence of the role of the endocannabinoid (EC) system in the regulation of mood due to its role in the balance of cortical excitation and inhibition.
Anandamide, tetrahydrocannabinol (THC) and cannabidiol (CBD) have antidepressant, antipsychotic, anxiolytic, analgesic, anticonvulsant actions. This suggests there may be a treatment opportunity in mood and related disorders and this is proposed in this paper.
Post mortem and other studies have shown EC abnormalities in people suffering from depression, schizophrenia and in those who have committed suicide. Abnormalities in the cannabinoid-1 receptor (CNR1) gene that codes for cannabinoid-1(CB1) receptors are reported in psychiatric disorders.
There is limited evidence showing the efficacy of exogenous cannabinoid treatments in psychiatric disorders but it seems suggestive of a possible benefit. Further research is needed to see if there is benefit.
Acta Psychiatr Scand. 2011 Oct; 124 (4): 250-61. doi: 10.1111/j.1600-0447.2011.01687.x. Epub 2011 Mar 9.
PMID: 21916860 [PubMed – in process]

5. Drugs for depressed children and teenagers
Antidepressants are used in younger patients for the treatment of psychiatric disorders particularly in more severe cases. Non-pharmacological methods such as psychotherapy are more likely to be used for mild to moderate symptomatology. This paper reviews the drug choices.
In general, it is suggested that the first-choice medication for the treatment of juvenile unipolar depression is the selective serotonin reuptake inhibitor (SSRI) fluoxetine, which is recommended due to its efficacy and approval. Second-choice SSRIs include sertraline, escitalopram and citalopram are recommended.
Tricylics, alpha-2-adrenoceptor antagonists and SNRIs are alternative second choice options.
Taurines R, Gerlach M, Warnke M. World J Biol Psychiatry 2011 Sep;12 Suppl 1:11-5.
PMID: 21905988 [PubMed – in process]

6. Suffering in Silence
Many people don’t go to their doctor about their depression.
In this study in California, a telephone survey was conducted of over a thousand adults that were part of a previous behavioural survey.
The people were asked about their reasons for not disclosing symptoms, their beliefs related to depression-related beliefs and demographic characteristics.
The most frequent reason given was that they did not want to be prescribed antidepressants.
Those who did not have a history of depression said that depression falls outside the remit of primary care and that they were worried about being referred to psychiatrists.
Those who were clinically depressed had more personal barriers to seeking help than those without symptoms of depression.
Various socioeconomic factors had an influence including being female, poorer, negative or stigmatising beliefs about depression, symptom severity, and absence of a family history of depression.
The conclusions from this study is that many people are negatively predisposed to disclose their depression to doctors. Interventions should be encourages to get people to tell the doctor about their depression and doctors should ask specifically about it.
Bell RA, Franks P, Duberstein PR, et al. Ann Fam Med 2011 September-October; 9(5): 439-446.
PMID: 21911763 [PubMed – as supplied by publisher].

7. Effect of prayer on depression
In a European wide study, the impact of religiosity on depression was examined in people over 50. Using evidence from some simple models it has been suggested that may be religiosity, as measured by the frequency of prayer, is associated with a higher level of depression. These models however did not separate cause and effect, ie is the increased praying due to the presence of depression as opposed to vice versa. In this study, a model was developed using a different design to circumvent this. The authors found that prayer has a positive effect in that it leads to a lower level of depressive symptoms.
Denny KJ. Soc Sci Med 2011 Aug 26. [Epub ahead of print]
PMID: 21911275 [PubMed – as supplied by publisher]

8. Sleep, Mood and Anxiety
There is a known link between sleep disturbance and anxiety and depression. But little is known of the cause of this link.
In this study, the genetic and environmental influence on this association was estimated.
Using 1556 young adults (both twins and sibling pairs) questionnaire found sleep disturbance was moderately correlated with symptoms of anxiety and depression.
It was found that there was a major influence in the genes that affect the symptoms of sleep disturbance and of anxiety and depression. In particular in the case of the anxiety link it was found the genes played a greater role.
The authors concluded that although sleep disturbance is related to the presence of various psychiatric difficulties, it should be treated and considered independently.
Associations between sleep quality and anxiety and depression symptoms in a sample of young adult twins and siblings
Gregory AM, Buysse DJ, Willis TA et al. J Psychosom Res 2011 Oct; 71(4): 250-5. Epub 2011 May 20.
PMID: 21911103 [PubMed – in process]

9. Is Trial Evidence Really Best for Bipolar?
The randomized clinical trial (RCT) is the established to study human treatments, but there are a number of biases and limitations to this approach.
In this study, all of double-blind RCTs for treating bipolar were reviewed in journals with a high impact factor. Thirty articles were reviewed.
Small numbers less than 50 and pharmaceutical sponsorship of papers were two biases highlighted. The authors said these treatment studies and the limitations hinder their clinical usefulness and compromise the consistency of the findings.
Strech D, Soltmann B, Weikert B, et al. J Clin Psychiatry. 2011 Jun 25. [Epub ahead of print]
PMID: 21294992 [PubMed – as supplied by publisher]

10. Zinc deficiency and depression
Postgraduate students were investigated to see if there dietary zinc levels were associated with depression. Four hundred and two students were studied. An inverse relationship was found between zinc levels and depression which held when it was controlled for potential confounders. The authors suggest that long term zinc deficiency may modulate depressive symptoms.
Yari T, Aazami S. Biol Trace Elem Res. 2011 Sep 20. [Epub ahead of print]. Dietary Intake of Zinc was Inversely Associated with Depression.
PMID: 21932045 [PubMed – as supplied by publisher]

Genetics of Psychiatric Disorders

The stigma of mental disorders still puts proactive policy in terms of mental wellness promotion on the long finger in many countries. The conditioned approach of burying heads in sand is the norm. Surely the time is nigh for change with recent research beginning to elucidate the complex heritable components of disease?

Disorders of the mind are complex. The traditional view that the brain is a mysterious black box is being dispelled more and more each day as the wiring mechanisms of the brain are delineated.

• Discrimination is Clinical

The clinical expression of psychiatric disorders is distinctive, and yet there is often a great difficulty to diagnose disorders. There is much commonality between the major psychiatric disorders despite there being typical symptoms in specific disease classifications.

There is overlap in the clinical features of many of these conditions. Schizophrenia and bipolar disorder share many clinical features. There is some overlap between schizophrenia and autism. In early definitions of schizophrenia, autism features were included in the diagnosis.

Despite this clinical overlap, there are differences that make them clearly definitive diagnoses. There may be clear age of onset differences between some disorders; they may have different prevalence. They have different treatments and can have distinct outcomes.

• Gene versus Environment

The involvement of brain chemical defects is undeniable in many cases of mental disorder, but it is not clear how much such defects play a role. In many cases, there is an unclear distinction between core neuropsychiatric disorders genes and psychological conditions and reactions due to environmental exacerbators, such as stress.

• Genetic Tools

With new genetic tools, including genome wide analysis and relatively much cheaper methods of sequencing whole genomes and exons (bits of coding DNA), coming onstream novel candidate genes are being identified as potential causative agents in mental disease all the time. The result is not surprisingly that there is more complexity than expected.

• Risk Haplotypes

Mutations in specific genes that may cause damage have been found to be common to a number of psychiatric disorders. Clinical similarity is in part due to these shared causative genes or associated genes or risk haplotypes. This bears up with the genetic studies as certain risk haplotypes or groups of genes that link together have been shown to be inherited in families with mental disorders. DISC1 is a gene that has been shown to be linked to a variety of psychiatric disorders.

What is surprising from genetic studies is that the same gene can have a different role depending on its segregation with a specific disease or severity of disease. If it is knocked out or its function absent it may for example cause a severe brain disorder; if it is partially functional it may cause a mild autism.

• Role for Alleles

Allele variation throughout the coding and non-coding parts of the genome seems to be important. It can determine if there is schizophrenia of a milder or more severe type.

This makes treatment more complex as it may not just be mutation of a gene itself but involvement of other parts of the genome involved in regulation of that gene. Factors such as copy number and regulation of translation of a specific gene may come into play.

• What Fraction is Known?

The upshot is that there will be no one magic drug or fix on a population basis to fix a single defective gene causing a major psychiatric disorder. We may never be able to cure all schizophrenics or people with autism. Life is never that easy. The vast majority of autism and schizophrenia cases are not yet diagnosed by genetics. It has been suggested that we have only identified a fraction of the genes involved anyhow.

This does not mean that individual treatments will have a profound effect on an individual case by case. Some powerful medications have a significant impact on mental disease already, whereas others have little or no impact. Treatment choice remains a conundrum.

• Probing Early Development

Research into the normal early development of the brain will provide clues as to how diseases develop, but most research focuses on diseased individuals. Mutations of many genes involved in neuronal development can lead to psychiatric disorders but we need to know what is normal. Basic research should focus on how the wiring of the brain mediates functions and then we can determine what happens when those processes go wrong.

Although only a fraction of gene involvement can be explained so far, it seems that many of the candidate genes are involved in the brain plasticity. Plasticity includes mechanism of adaptation and rebuilding.

• Metabolic Comorbidity

Known metabolic risk markers have also been associated with psychiatric disorders. Certain gene mutations are associated with increased risk of cardiovascular disease and other metabolic conditions and these have been found in patients also with neurodevelopmental disorders including autism and schizophrenia. These metabolic risk factors include obesity, glucose abnormalities and raised lipid levels.

Diabetics do tend to have a more severe course of mood disorders, and more psychiatric hospital stays per lifetime. Perhaps it is burden of disease or it may be commonality of genetic cause, but diabetics with bipolar get more rapid cycling and has a more chronic condition rather than a more episodic course.

• Focus on Autism

Autism spectrum disorders (ASD) have a widely variable presentation. It is highly heritable as defined by twin studies. One twin has autism then a monozygotic twin has somewhere between 60 and 90% chance of having some form of ASD. Despite a particular genetic cause of autism is uncovered in 15% of those diagnosed with autism. So without marker genes and clear diagnosis and the wide spectrum of symptomatology it is most likely that much ASD remains a missed diagnosis.

Removal of funding for schools for support teachers for autism and behavioural disorders and monies for counselling services for the mentally ill will return Ireland to a prehistoric sort of management.

• Medieval Mental Management

Ireland remains in ignorant bliss of its negligence to the vast majority of these so-called ‘mentally disabled’ children who will become its future.

There is a dearth of affordable community counselling services for people with a range of problems from depression to bipolar disorder.

Psychiatric illness, although considered for so long to be a mental disability in Ireland, has a huge spectrum that affects a large proportion of the population. Some of these conditions are severe and others are mild.

Genetics may eventually provide some of the answers as to the causes of these disorders, but there is a continuum of symptoms that need to be tackled and not ignored to improve patient quality of life.

KEY POINTS

• There is symptom overlap between different psychiatric disorders and yet there are clear distinctive clinical diagnosis.
• The genetics of psychiatric disorders is complex and only a small proportion of genes involved have been elucidated.
• Some genes are involved in seemingly diverse psychiatric disorders and may also be involved in certain metabolic conditions.

Conor Caffrey is a medical and science writer who has recently been diagnosed with bipolar 2.  This article is after several presentations on the genetics of psychiatric disorders at the recent Wiring the Brain Conference held in Powerscourt, County Wicklow.

Related articles

• Identifying The Genes Responsible For Autism Disorders Is Critical For Diagnosis And Treatment (medicalnewstoday.com)
• Asperger’s and Autism (realintent.org)
• Some autism behaviors linked to altered gene (sciencedaily.com)