Chapter 18: Affective Disorders: Antidepressants and Mood Stabilizers Flashcards
What is the genetic contribution of depression?
The heritability of depression is 40-50% and family history is the greatest predictor of vulnerability.
What neural abnormalities is depression associated with?
Depression is associated with abnormalities of HPA axis function including:
- high plasma ACTH and cortisol
- hypersecretion of CRF
- flat circadian rhythm of cortisol
- failure of dexamethasone-induced negative feedback
How is depression related to sleep?
- onset insomnia
- reduced slow-wave sleep
- early onset of REM sleep
- more frequent and longer REM episodes early in the night
- more vigorous eye movement during REM
How is mania related to sleep?
- very little sleep without loss of energy
2. sleep deprivation initiates a manic episode
Why is it difficult to develop animal models of affective disorders?
- the underlying neurobiology is unclear
- neurochemical and neuroendocrine abnormalities are insufficiently consistent to use as diagnostic markers
- antidepressants that work in rodents do not work for humans
- animals models only reflect a few depressive behavioural symptoms, not all of them that humans have
What is the monoamine hypothesis of mood disorders?
Depression is associated with low levels of monoamines, whereas mania coincides with excess monoamine activity. This hypothesis does not explain the discrepancy in time between the rapid increase in monoamines by antidepressant drugs and the slow onset of clinical effects over several weeks.
What evidence is there for the role of serotonin in depression?
- lower 5-HIAA occurs in depressed individuals
- knockout mice show some behaviours analogous to human depression
- depletion of tryptophan causes depressed mood in patients in remission
- a polymorphism of the serotonin reuptake transporter (SERT) gene is associated with depression
- increased postsynaptic 5-HT2 receptors are found in patients postmortem
What effects do chronic antidepressant treatment have?
- down-regulation of 5-HT autoreceptors, which increases synaptic 5-HT and subsequent intracellular changes leading to neurogenesis and synaptic remodeling
- increase rate of firing and NE release, which leads to down-regulation of β-adrenergic receptors and α2-autoreceptors
- up-regulate the cAMP cascade, leading to increased expression of BDNF
What is the serotonin-norepinephrine hypothesis of depression?
Anatomical and functional interactions exist between the serotonergic neurons in the raphe nuclei and the noradrenergic neurons in the locus coeruleus. The two systems are capable of modulating each other.
What is the glucocorticoid hypothesis of depression?
Prolonged hypersecretion of CRF, ACTH, and glucocorticoids damages dendritic branching and spines in the hippocampus and PFC. It also reduces neurogenesis in the hippocampus, which further diminishes the negative feedback on HPA axis function.
What is the neurotrophic hypothesis of depression?
The neurotrophic hypothesis suggests that stress hormones that reduce BDNF may cause neuronal damage, and antidepressants may prevent it by elevating BDNF.
What is the evidence for the role of BDNF in depression?
- BDNF is low in the hippocampus and the PFC of depressed patients postmortem
- a BDNF gene polymorphism may be associated with mood disorders
- modifying BDNF gene expression in mice leads to depressive behaviours
What are the therapies used to treat affective disorders?
- Monoamine oxidase inhibitors (MAOIs)
- Classic tricyclic antidepressants (TCAs)
- Selective serotonin reuptake inhibitors (SSRIs)
- Atypical antidepressants
- Electroconvulsive shock and transcranial magnetic stimulation
- Lithium (bipolar disorder)
How effective are antidepressants at treating depression?
Antidepressants of all classes reduce symptoms in about two-thirds of individuals after 4 to 6 weeks of treatment. Total remission of symptoms occurs less often. Continued treatment prevents relapse.
How do MAOIs work?
MAOIs elevate brain levels of monoamines by inhibiting the MAO enzyme in the presynaptic terminal which increase the amount available for release. Over time this leads to down-regulation of amine receptors and upregulation of the cAMP second-messenger system.
