Affective Disorders: Antidepressants and Mood Stabilizers

major depressive disorder (MDD) (3)

• recurring episodes of dysphoria + negative thinking → reflected in bhvr

• characterized by overwhelming sadness, feelings of worthlessness, loss of interest in normally pleasurable activities

• most common disabling mental disorder in adults → responsible for 50% of suicides

prevalence of MDD (4) country, gender, demographics

• higher in high-income countries

• Canada: 11% lifetime prevalence

  • women 2x as likely → may be under diagnosed in men

  • higher in young, single, unemployed, Indigenous ppl

how does MDD damage quality of life (4)

• extensive overlap of depression/anxiety + alcohol dependence

• comorbidity predicts more severe symptoms

• episodes recur throughout life

• incidence ↑ age of onset ↓ since 1955

bipolar disorder (BPD) → describe mania (4)

• cyclic mood swings from depression to mania

• mania feels faultless, full of fun, talkative, energetic, need for sleep ↓

• 1º mood is irritability, belligerence, impatience

• bhvr: reckless driving, buying sprees, foolish business deals, sexual indiscretions

heritability of mood disorders (2)

• twin studies: 65% concordance rate for identical twins → 80% for BPD

• no single gene for affective disorders → vulnerability genes may contribute small amounts

risk factors for mood disorders (4)

• stress: mediated by HPA axis

• elevated cortisol lvls + abnormal circadian rhythm in cortisol secretion

• early life stress alters HPA axis set point = permanently overly responsive

• failure to respond to dexamethasone challenge

dexamethasone (3) + how do depressed individuals react to a challenge (1)

• synthetic glucocorticoid

• should act as a negative feedback stimulus to suppress hypothalamic release of CRF and pituitary release of ACTH,

• resulting in decreased cortisol levels

• Depressed individuals fail to respond with reduced cortisol levels after injection with 1 mg dexamethasone (DEX).

how do biological sleep rhythms ∆ in depressed individuals (4)

• abnormal sleep cycles

• biological clock may be phase shifted

• altered sleep rhythms

  • BPD: sleep deprivation can trigger an episode of mania

potential involvement of gut-brain axis in depression

• gut bacteria can directly/indirectly impact CNS function through interaction w vagus cranial nerve

• mice lacking intestinal bacteria = ↑ response to stress

• different bacterial flora = variety of psychiatric symptoms

neuroanatomy ∆s of MDD (5)

• smaller volumes

  • basal ganglia

  • thalamus

  • PFC

  • hippocampus

  • anterior cingulate cortex

psychological factors affecting mood disorders (what is the negative cognitive triad) (3)

• negative cognitive triad → distorted pessimistic view of themselves, world, future

• interpersonal factors: deficits in social skills/communication problems

• stressful life events

social factors affecting mood disorders (7)

• poverty

• adverse work conditions

• trauma

• drug/alcohol use

• lack of social support

• childhood abuse

• stress of prejudice

symptoms of MDD (9)

– Sadness, despair, depressed mood
– Guilt, anxiety, low self-esteem
– Lack of motivation, fatigue, loss of energy
– Loss of interest or pleasure in activities
– Diminished ability to concentrate
– Changes in appetite or weight
– Disrupted sleep patterns
– Recurrent thoughts of death or suicide attempts
– Physical symptoms such as fatigue, headache, or GI problems

diagnosis/prognosis of MDD (4)

diagnosis

• at least 5+ symptoms persisting for at least 2 weeks → impair functioning

• can be mild/moderate/severe

prognosis

• chronic + recurrent

• associated w shorter life expectancy

“How are bipolar/mania modeled in animals?” (4)

• Disrupted circadian rhythms

• sleep deprivation → mania-like behavior reduced by lithium

• CLOCK knockout mice

• glycogen synthase kinase-3 (GSK-3) overexpression. → lithium targets this

monoamine theory → why is it outdated (5)

• low lvls of 5HT, DA, NE in CNS responsible for depressed mood

  • many drugs used to MDD affect 5HT system

  • mania coincides w excess monoamine activity

• simplistic + misguided

  • discrepancy in time btw rapid increase in monoamines by antidepressant drugs + slow onset of clinical effect over several weeks

how does 5HT dysfunction contributes to mood disorders (4)

• Low 5-HIAA is often found in depressed people. (5HT metabolite)

• If you genetically remove tryptophan hydroxylase (enzyme that makes 5-HT) or certain 5-HT receptors in mice → they show depression-like behaviours in animal tests.

• tryptophan deficient diet causes depression in individuals w fam history

• ↑ density of 5HT receptors in post mortem brains of unmedicated depressed patients (upregulated)

  • the brain adding more receptors when serotonin signaling is too low (trying to compensate).

a polymorphism in the _____ gene may contribute to development of depression → short allele + ______ = _______ but studies are inconclusive

• SERT

• stress

• greater risk of depression

what explains the delay in therapeutic onset of SSRIs (2)

• acutely: autoreceptors ↓ 5HT synthesis

• chronic treatment = autoreceptor downregulation

acute effects of antidepressants on 5HT cells (3)

1. reuptake transporter blocked by antidepressants = more 5HT at synapse

2. activated autoreceptors reduce 5HT synthesis + release

3. little ∆ in 5HT action

chronic effects of antidepressants of 5HT cells (3)

1. reuptake transporter continues to be blocked

2. autoreceptors downregulated = ↑5HT release

3. more 5HT = greater postsynaptic effects

how is NE activity altered by antidepressants (3)

• down regulation of ß receptors

• untreated individuals + BPD = increased density of a2 autoreceptors

• More α₂-autoreceptors = stronger brake → less NE release.

• Where do NE vs 5-HT neurons originate? Modern hypothesis of modulation (2)

• originate in NE: LC; 5-HT: raphe nuclei.

• Modern hypothesis: depression involves both serotonin & NE, which modulate each other.

neurobiological models of depression (5) DMN vs salience networks

• ↓ volume of hippocampus + other brain regions

• abnormal lvls of metabolic activity

• highly coupled connectivity btw nodes in default-mode network (DMN) = introspective thinking

• When DMN activity goes up, salience network activity tends to go down.

  • When the salience network ramps up (you notice something important / switch to an external task), DMN usually quiets down.

stress + prolonged hypersecretion of ___________ damages _____ branching + ____ in _____ and ____ → elevated _______ reduces the formation of ________→ neurotrophic hypothesis: these things may be due to low _____ which antidepressants prevent

1. CRF, ACTH, glucocorticoids

2. dendritic branching + spines

3. hippocampus + PFC

4. cortisol

5. new hippocampal cells (neurogenesis)

6. BDNF

evidence for BDNF in the etiology of depression includes (3)

• is low in hippocampus + PFC of depressed patients post-mortem

• BDNF gene polymorphism may be associated w mood disorders

• modifying gene expression in mice = depressive bhvrs

how can BDNF gene be modified (epigenetic ∆s) (3)

• chromatin remodelling that affects lvls of gene expression

• chronic stress = long-lasting ↓ in BDNF my ↑ histone methylation = closed chromatin state that ↓ses transcription

• reversed by antidepressants

how do chronic antidepressants affect the cAMP pathway (3)

• upregulate cascade despite downreg of ß-adrenergic/ 5HT receptors that are coupled to the cAMP cascade

• increases phosphorylated CREB → ↑BDNF

• enhances the cAMP by inhibiting PDE produced antidepressant effects

_____ are the oldest antidepressant drugs → inhibition of MAO = ____ in the amount of NT available for release BUT neuron adaptation involving ∆ in _____ or ____ function must play a role in effects → examples (3)

1. MAOIs

2. increase

3. receptor density

4. 2nd messenger function

5. Phenelzine (Nardil), tranylcypromine (Parnate), isocarboxazid (Marplan)

side effects of MAOIs (4)

1. ∆s in bp, sleep disturbances, overeating/weight gain

2. ↑NE lvls intensify drugs that enhance NE function ie. cocaine, cold meds

3. ↑lvls of tyramine releases more NE at nerve endings = ↑bp dangerously

4. inhibition of other liver enzymes

how do tricyclic antidepressants (TCAs) block the reuptake of NE/5HT (3)

• bind to presynaptic transporter protein → inhibit reuptake of NTs = pronlonged action

• ↓lvls of ACh, histamines

• acute increase in synaptic activity in 1st step in antidepressant action → neuronal adaptation over time necessary

side effects of TCAs (4)

• histamine receptor blockade = sedation

• anticholinergic effects = dry mouth, constipation, dizziness

• alpha 1 blockade coupled w NE reuptake blocking = potentially dangerous cardiovascular effects

• OD= cardiovasc. problems, delirium, convulsions, coma, death, low therapeutic index

side effects of SSRIs (4)

1. ↑sed 5HT at some receptors = anxiety, movement disorders, muscle rigidity, nausea, headache, insomnia, sexual dysfunction

2. serotonin syndrome: potentially life-threatening when combined w other 5HT agonists

3. can cause dependence

4. only good for severe depression → not moderate/mild

SNRIs (3)

• modulate NE/5HT = more beneficial

• mirtazapine blocks alpha2 autoreceptors = ↑ synaptic NE + a2 heteroreceptors on 5HT cells = ↑5HT

  • blocks only selective 5HT receptors to ↓ side effects

ketamine as an antidepressant

• effects last longer than drug’s half life

• enhances BDNF-stimulated neurogenesis + elaboration of dendritic spine growth

  • may be due to rapid activation of the mTOR signalling cascade

ADDs are absorbed from _____ + undergo _____ by the ____ system → they raises lvls of _______ + have serious effects if taken with ______ that also raises lvls of monoamines → stoping them abruptly may cause ________

1. GI tract

2. first-pass metabolism

3. cytochrome P450 system

4. monoamines

5. food/drink (ie. high in tyramine or MDMA)

6. antidepressant discontinuation syndrome

all ADDs affect ________ at the synapse → exert _____ effects by increasing the ______ of newly formed neurons in ________→ can also help by normalizing the lvls of _______

1. amount of NT

2. antidepressant effects

3. growth + survival

4. hippocampus

5. stress hormones

ADD use + pregnancy (3)

• increased risk of spontaneous abortion, preterm birth, low birth weight

• untreated maternal depression = same outcomes

  • worsen maternal care, poor nutrition, alcohol exposure, decreased bonding w infant

how does lithium for treating BPD stabilize the highs/lows (5)

• lithium: most effective treatment for BPD

• eliminates/reduced manic episodes w/o causing depression/producing sedation

• effective in reducing suicide

• mild side effects

• v low theraputic index → toxic effects can be severe → needs monitoring

lithium mechanism of action (3)

• enhances 5HT actions

• reduces catecholamine activity

• mood stabilizing due to inhibition of GSK-3 reg of circadian rhythms

other treatments include ____(4)

• anticonvulsants ie.

  • valproate: as effective as lithium → teratogenic

    • increases GABA lvls by stimulating glutamic acid decarboxylase + inhibiting GABA transaminase

  • carbamazepine: as effective as lithium

    • inhibits NE reuptake = blocks + upregulates adenosine receptors