Introduction to the complex world of mood Flashcards
What are affective disorders?
Neuropsychiatric conditions broadly divided into 2 conditions:
- Depressed mood (MDD, clinical, unipolar, or major depression)
- Bipolar disorder
= Mood disorders
- conditions characterised by a disturbance in one’s mood
What do the DSM and ICD offer?
- Common language, standard criteria
- help mh professionals determine/communicate patient’s diagnosis - Diagnostic criteria for research
- Resource for health insurance, pharmaceutical companies, and legal system
What are the comorbidities associated to affective disorders?
- Anxiety disorders
- Substance use disorders
- Impulse control disorders
What is the association between mood disorders and dementia?
Increased risk of dementia
- over 60,000 individuals, depression associate with 2-fold increased risk of developing dementia in older age
How does the identification of correlates and causes differ in mood disorders?
Correlates are more easily identifiable than causes in mood disorders
What is aetiology of an affective disorder?
> Nurture: environment/experience
> Nature: genes
What can improve our understanding of affective disorders?
> Engagement and communication with patients and their families
> Evaluation of underlying biological factors
How can you evaluate the underlying biological factors of affective disorders?
- Examining patients’ blood, saliva, hair, nails, urine, faecal matter
- Imaging techniques (patients vs. controls)
- Post-mortem sampling
- iPS cells
- Use of genome association and animal models
What is the benefit of using animal models for understanding mood disorders?
> Provide behavioural readouts
> Enhance understanding of biological underpinning through brain-behaviour associations
> Help identify new underlying pathways, drug targets, test protective interventions
What are the four types of environmental manipulations (procedures) we can operate in animal models?
> Social isolation
> Unpredictable chronic mild stress
> Social defeat (introduction of agressive animal)
> Physical manipulations
- restraint stress
- maternal deprivation
- sleep deprivation
What are the three types of internal alterations we can operate in animal models?
> Permanent
- olfactory bulbectomy (removal of olfactory bulb)
- adrenalectomy (removal of adrenal glands)
> Transient
- manipulation of immune/stress systems
- disruptions induced by changing dietary composition
> Genetic modifications
Which genetic modifications can be made in animal models?
> Transgenic and knock-out animals with genetically altered systems
> Selection of extreme types from an animal population
> Use of inbred strains
What is the purpose of pharmacogenetics?
Identify genetic variants that control efficacy and possible adverse reactions to drugs
What is the genetic contribution to unipolar depression (Craddock and Forty, 2006)
Between 33-42%
What is the genetic contribution to bipolar disorder (Craddock and Forty, 2006)?
Between 80-90%
What did the mega-analysis of genome-wide association studies for major depressive disorders (Ripke et al., 2013) show?
> No single nucleotide polymorphisms (SNPs) reaching genome-wide significance
> Lack of result might be due to underlying heterogeneity of MDD cases part of the study
What is the limit of most studies that try to identify the genetic contribution to depression?
- Insufficient power
- Need of large sample size and/or decrease in heterogeneity of selected cases
Which neuroimaging techniques indirectly measure neuronal activity?
- PET
- SPECT
- fMRI
Which neuroimaging techniques directly measure electrical activity?
- MEG
- EEG
How do PET and SPECT scans indirectly measure neuronal activity?
Look at distribution and density of neurotransmitter receptors in certain areas
How does grey matter vary in depressive disorders (Redlich et al., 2014)?
Individuals with bipolar depression (BD) had decreased grey matter in sagittal and coronal slices of hippocampus and amygdala
vs. those with unipolar depression UD)
What is the effect of electroconvulsive therapy (ECT) on the cortical structures of patients with major depression (Joshi et al., 2016)?
- Patients with refractory depression showed smaller hippocampal volumes at baseline compared to controls
- Increase in hippocampal and amygdala volumes after ECT treatment in relation to improvement in symptoms
What is the National Institute for Health and Care Excellence (NICE)?
Public organisation which is part of Department of Health in UK
- helps clinicians to choose the best therapies for their clients based on research, therapeutic outcomes, and health economics
What is the leading cause of disability worldwide according to the World Health Organization (WHO, 2018)?
Depression
- high rate of relapse despite wide range of psychological/pharmacological treatments available
What is the monoamine hypothesis of depression?
Depression is due to deficiency of neurotransmitter levels or signalling in the brain
How did the monoamine hypothesis of depression emerge?
- First antidepressants (isoniazid, iproniazid) first used as medication for tuberculosis in 1950s
- Doctors noticed patients using this medication showed improvement in mood
- it inhibited monoamine oxidase (break down enzyme of monoamine NTs)
-> it was concluded that depression likely caused by lack of neurotransmitters
What are the three major monoamine neurotransmitters?
- Serotonin (5HT)
- Dopamine (DA)
- Norepinephrine (NE)
What makes serotonin, dopamine and norepinephrine monoamines?
They all have an amino group.
What were the common misconceptions on neurons?
> Number of neurons in adult brain fixed in early life, with majority formed during pre-natal and perinatal stages
> Neuroplasticity in nervous sustem achieved by ‘strengthening’ without any addition of new neurons
Which theories emerged from the discovery of adult neurogenesis ?
> Neurogenesis hypothesis/alterations
> Hypothalamic-pituitary-adrenal axis dysfunction
> Inflammatory alterations - Macrophage Theory of Depression
> Oxidative stress system alterations
What does the neurogenesis hypothesis (alterations) of depression propose?
Changes in neurotransmission occur shortly after intake of antidepressants
BUT effects take 2 to 6 weeks
-> depression cannot be solely due to a lack of neurotransmitters
Which findings support the adult neurogenesis explanation of depression?
> Altered rates of neurogenesis in adult hippocampus might underlie either development of major depression or recovery from it
- stress / raised glucocorticoids decrease neurogenesis and increase depression levels
- antidepressants and exercise increase neurogenesis and decrease depression levels
> Antidepressants increase neural progenitor cells in human hippocampus
- low numbers of new neurons in individuals with depression
- increased number of new neurons in individuals taking tricyclic antidepressants
What is the association between adult neurogenesis and mood (Borsini et al., 2015)?
Process of neurons growing and forming new connections
- takes several weeks
- AND is associated with improvement in mood
What did animal studies show on the effects of antidepressants and depression treatment (e.g. ECT)?
Antidepressants and treatment for depression (e.g. ECT) induce growth and enhanced branching of neurons in hippocampus
(cf. increased size of hippocampus)
What is oxidative stress?
Consequence of biological imbalance between oxidants (Reactive Oxygen Species, ROS) and antioxidants
What are the effects of oxidative stress?
> Decreases neurogenesis
> Can lead to loss of control in intracellular signalling pathways
What do intracellular signalling pathways refer to?
Extracellular stimuli can induce chain of reactions which transmits signals from cell surface (through ligand binding, G-protein receptors) to intracellular target enzymes (including transcription factors)
= intracellular signal transduction
-> alters the regulation of gene expression
What is the evidence on the association of depression and oxidative stress?
Meta-analysis of observational studies (Palta et al., 2014):
- correlation between depression and different levels of oxidative stress in individuals
Which approach is most beneficial to individuals suffering of affective (mood) disorders?
A holistic approach
- psycho-social factors, culture
- nutrition
- genetics
- inflammation
- early trauma
- endocrine and immune system
- oxidative stress
