Chapter 18: Affective Disorders Flashcards
Affective Disorders
Major Depressive Disorder
Bipolar Disorders
Neurobiology of Major Depressive Disorder (MDD)
The role of stress and the stress hormone, cortisol
The monoamine hypothesis
The neurotrophic hypothesis
The monoamine hypothesis is […]
The monoamine hypothesis is mostly wrong
- reduced levels of monoamines in CNS
- tricyclics and SSRI antidepressant (AD) mechanisms
- SNRIs and “new generation” ADs
Mania
Excess MAO activity
Environmental stressors activate a stress response
- activation of the HPA axis
- CRH released from the hypothalamus initiates a cascade that results in cortisol release from the adrenal glands
- cortisol levels are reduced via negative feedback, involving the hippocampus
- normally follows a circadian rhythm
- family history is strongest predictor of vulnerability
[…] is altered with depression
Biological clock is altered with depression
- found in suprachiasmatic nucleus of hypothalamus
Early life stressors alters set point of HPA, […]
Early life stressors alters set point of HPA, making it overly responsive and increased risk for depression, anxiety, and alcohol use
The best- established abnormality of the HPA axis in MDD is […]
The best- established abnormality of the HPA axis in MDD is an over-secretion of cortisol
- blood levels of cortisol are normally reduced by dexamethasone
- some people with MDD fail to suppress cortisol following dexamethasone
- the endocrine system is signaling chronic stress because the negative feedback system is inefficient
- high levels of cortisol is characterized by abnormal circadian rhythm in cortisol secretion
Dexamethasone
Synthetic glucocorticoid that should act as negative feedback stimulus to decrease CRF and ACTH release
Depression is associated with atrophy in […]
Depression is associated with atrophy in hippocampus
- stress increases cortisol levels, which leads to decreased BDNF
- less BDNF causes neuronal atrophy and decreased neurogenesis
Chronic stress causes atrophy of cortical neurons
Restraint stress: reduced dendritic length and branching of mPFC neurons
BDNF: polymorphism, which reduced the effects of BDNF, mimics stress-induced damage
- Both stress and the BDNF polymorphism result in depression-like and anxiety-like behavior in rodents
Neurotrophic hypothesis
Less BDNF may be responsible for loss of dendritic branches and spines in hippocampus and PFC
Both […] result in depression-like and anxiety-like behavior in rodents
Both stress and the BDNF polymorphism result in depression-like and anxiety-like behavior in rodents
Anhedonia- sucrose preference
Anxiety- novelty-suppressed feeding
[…] are involved in depression
Neurotrophins are involved in depression
*Chronic stress causes elevated cortisol, which reduced BDNF levels and activity, leading to neuronal atrophy and decreased neurogenesis
MDD Remission: therapeutic lag
Antidepressants:
- increase synaptic levels of NE and 5-HT, but is not primary therapeutic mechanism
Alternative hypothesis:
- Receptor adaptations: biochemical and genetic changes that alter synaptic structure and function
- AD- induced neurogenesis in the hippocampus
AD treatment promotes […]
AD treatment promotes dendritic branching and increases neurogenesis
- Neurogenesis in the hippocampus is proposed to be the “slow step” of therapeutic lag
- ADs increase synaptic levels of 5-HT and NE
- increased expression of BDNF
Glucocorticoid hypothesis
Focuses on stress-related neuroendocrine abnormalities
Mechanism of AD’s according to the neurogenic hypothesis: stress-induced damage is repaired
Chronic AD —>
5-HT and NE levels are increased —>
Increases BDNF expression —>
Repaires the stress-induced damage
Serotonin Vulnerability
- low levels of 5-HT only cause depression in already vulnerable populations
- SERT: short allele is associated with decreased level and function of transporter
- Receptor binding studies in unmediated individuals: increased postsynaptic 5-HT2 receptors
Chronic stress reduces […], altering structure and function of […]
Chronic stress reduces BDNF, altering structure and function of mPFC and hippocampus
- most consistent chronic effects of AD: down-regulation of B-receptors and 5-HT2 receptors
Major classes of AD drugs
Monoamine oxidase inhibitor (MAO-I)
Tricyclics antidepressant (TCA)
Selective serotonin reuptake inhibitor (SSRI)
New generation AD’s (dual-action, multi-action)
Selective norepinephrine reuptake inhibitor (NRI)
Monoamine oxidase inhibitor (MAO-I)
Last resort AD
Phenelzine (Nardil), tranycypromine (Parnate), and isocarboxazid (Marplan)
FDA-Approved Psychiatric Medication in Past Decade
Oleptro (trazodone HCl) Viibyrd (vilazodone HCl) Trintellix (vortioxetine) Fetmiza (levomilnacipran) Rexulti (brexpiprazole) *add on for depression Spravato (esketamine; nasal spray); TRD Zulresso (brexanolone); PPD
Spravato (esketamine)
- for TRD
- Noncompetitive antagonist of NMDA receptors
- nasal spray (used in conjunction with oral AD)
- available only through the Spravato REMS
Zulresso (brexanolone)
- for PPD
- neuroactive steroid
- Positive allosteric modulator of GABAa- R
- continuous IV infusion over 60 hours
- headache, dizziness, somnolence
Acute Effects of ADs
- ) Reuptake transporter blocked by ADs leads to acutely more 5-HT in synapse
- ) Autoreceptors activated by increased synaptic 5-HT reduces 5-HT synthesis and release
- ) Effects cancel out and cause little change in 5-HT action
Class notes:
- SERT blockade elevates synaptic 5-HT
- 5-HT activates 5-HT1A autoreceptors
- slows cell firing and reduces 5-HT synthesis and release
Chronic effects of ADs
- ) Reuptake transporter continues to be blocked
- ) Autoreceptors are down-regulated and 5-HT release is increased
- ) Move 5-HT produced greater postsynaptic
Class notes:
- 5-HT1A autoreceptors down-regulate (internalize)
- 5-HT release gradually increases
- therapeutic lag
TCA therapeutic effects
Block the reuptake of NE and 5-HT
- differing affinity for SERT or NET
- unrelated to AD efficacy
TCA Drugs
Elavil (amitriptylin) Norpramin (desipramine) Tofranil (imipramine) Pamelor (nortriptyline) Vivactil (protriptyline) Surmontil (trimipramine) Anafranil (clomipramine)
TCA NET and SERT selectivity
1- more selective for NET
5- more selective for SERT
1- Norpramin (desipramine) 2- Vivactil (protriptyline) 3- Elavil (amitriptylin) 4- Tofeanil (imipramine) 5- Anafranil (clomipramine)
TCA side effects
(HAM) side effects due to non-selective antagonism:
- H1- sedation/ fatigue, weight gain
- a- AR- hypotension, arrhythmia
- mACh- dry mouth, constipation, dizzy
Low therapeutic index, lethal at 10x daily dose
SSRI Therapeutic Effects
Block the 5-HT transporter (SERT)
- more selective than TCAs
SSRI drugs
Prozac (fluoxetine) Zoloft (sertraline) Paxil (paroxetine) Luvox (fluvoxamine) Anafranil (clomipramine) Celexa (citalopram) Lexapro (escitalopram)
SSRI used in treatment for anxiety
Paxil (paroxetine) Luvox (fluvoxamine) Anafranil (clomipramine) Celexa (citalopram) Lexapro (escitalopram)
SSRI used in treatment of OCD
Paxil (paroxetine)
Luvox (fluvoxamine)
Anafranil (clomipramine)
SSRI side effects
Less severe than TCAs
- due to activity at several 5-HT receptor subtypes
- nausea, anxiety, insomnia, restlessness, headache
- frequently decreased libido and delayed orgasm and sometimes anorgasmia and arousal difficulties
SSRI Drug Specific Actions: Prozac
5-HT2c antagonism and may promote “activation” (good or bad)
SSRI Drug Specific Actions: Zoloft
DAT blockade is also “activating”
SSRI Drug Specific Actions: Paxil
Anticholinergic and NET blockade- anxiolytic
SSRI Drug Specific Actions: Lexapro
The purest SSRI
Serotonin syndrome
- potentially life-threatening
- agitation, ataxia, clonus, diaphoresis, tremor, disorientation, confusion
- ANS activity: fever, chills, elevated body/ hr
Discontinuation syndrome
- Dose is gradually tapered off to avoid withdrawal
- dizziness, nausea, diarrhea, fatigue, insomnia, increased anxiety, irritability
Increased half-life= increased syndrome (ex. Lexapro and Paxil)
* almost impossible with Prozac because of long half-life
Dual- action antidepressant Drugs
Oleptro/ Desyrel (trazodone)
Serzone (nefazedone)
Dual- Action AD Drug Action
- Serotonin Antagonist and Reuptake Inhibitor (SARI): blocks SERT and 5-HT2a and 5-HT2c receptors
- Sedating (H1); effective in treatment of depression- and anxiety-related insomnia
- 5-HT receptor antagonism reduces SSRI-like side-effects (priapism possible)
Dual-action antidepressants: SNRI
Effexor (venlafaxine)
Cymbalta (duloxetine)
Fetzima (levomilnacipran)
Effexor actions
- selectively boosts DA in PFC
- side effects resemble SSRIs more than TCA
Cymbalta actions
- selectively boosts DA in PFC
- side effects resemble SSRIs more than TCA
- anti-depressant in absence of pain
- analgesic in the absence of depression
Effexor Side- Effects
- SERT» NET
- nausea, sexual dysfunction
- TD: no adverse cardiac effect
- OD: can be lethal
Cymbalta side- effects
- SERT > NET
- Nausea, vomiting, night sweats
- start low; take with food
- cardiac and sexual side-effects are low
Fetzima side effects
- NET > SERT
- cardiovascular, sweating
- weight gain and sexual dysfunction uncommon
Dual-action antidepressants
Wellbutrin (bupropion)
Remeron (mirtazapine)
Wellbutrin (bupropion)
- NDRI: Ne and DA reuptake inhibitor
- cocaine-like action, but not reinforcing - Activating/ stimulating, generally without sexual side effects of SSRIs
Remeron (mirtazapine)
- blocks a2- AR to increase release of NE and 5-HT
- blocks 5-HT2 and 5-HT3 receptors to reduce side-effects
- SNRI+ Remeron= “California rocket fuel”
Multimodal/ partial agonist antidepressants
Viibyrd (vilazodone)
Trintellix (vortioxetine)
Viibyrd (vilazodone)
- SPARI: 5-HT1A partial agonist and reuptake inhibitory
- increased DA release and lesser degree of sexual dysfunction
Trintellix (vortioxetine)
Targets include:
- SERT antagonist
- 5-HT1A partial agonist
- 5-HT3 antagonist
- many others (NE, DA, ACh, H)
Viibyrd (vilazodone) Side Effects
- Nausea, GI discomfort
- insomnia
- no treatment emergent sexual dysfunction; may improve MDD- related dysfunction
Trintellix (vortioxetine)
- Nausea, GI discomfort; at higher doses- sexual dysfunction
- no clinically meaningful effects on weight gain, insomnia or somnolence, sexual or cardiovascular function
- Withhold 3d, restart at 1/2 dose
Is 5-HT1A receptor down-regulation that important?
Many receptors down-regulate:
- 5-HT1A and a2-AR autoreceptors - 5-HT2A and B-AR postsynaptic receptors
The time course of changing 5-HT levels depends on brain area
- Frontal cortex: decreased 5-HT at 1 week post-AD then increased 5-HT at 2 weeks - PFC, Hippo, VTA/Naac: increased 5-HT in 3 days
DOX
Allows Htr1A gene from coding for 5-HT1A autoreceptors
\+DOX= 1A-High -DOX= 1A-Low
Low 5-HT1A receptors
Faster onset (8d) of SSRI-induced changes in raphe firing rate and increased 5-HT release
- increased serotonergic tone - decreased behavioral despair - release to fluoxetine - models human C/C carrier
*resilient/ responsive
High 5-HT1A autoreceptors
Slower onset (26d) of SSRI-induced changes in raphe firing rate and 5-HT release
- decreased serotonergic tone - increased behavioral despair - no response to fluoxetine - models human G/G carriers
*vulnerable/ non-responsive
Monoamine nuclei are high interconnected and physiologically integrated
- “5-HT-NE hypothesis”
- LC neurons alter activity of raphe
- NE increases excitability of raphe neurons
- NE increases 5-HT output; low NE reduces 5-HT output
- Raphe neurons alter activity of LC
- overall effect of 5-HT is to inhibit (indirectly) LC output
The role of autoreceptors
Acute AD:
- decreased synthesis and release - worsen short-term symptoms
Chronic AD:
- down-regulation of many receptors - normal compensatory change or necessary for AD response? - explain the therapeutic lag?
Role of autoreceptor down-regulation
- is complex - multiple mechanisms involves in slow onset of AD drug effects
Ketamine is antidepressant
- a club drug also known as “special K”
- non-competitive NMDA receptor antagonist
- effects similar to PCP
- dissociative anesthetic, primarily used as a veterinary anesthetic
- at sub-anesthetic doses, IV ketamine produces a rapid but transient antidepressant effect
Ketamine effects are short-lived
The antidepressant effects last only a few days, no more than 1-2 weeks
Ketamine […] spine density on dendrites in […] 24 hours after administration
Ketamine increases spine density on dendrites in mPFC 24 hours after administration
- proposed role of BDNF/ TrkB
- AD effect lost in KO mice
- but other AD’s take weeks
- rapid activation of mTOR
- activation of AMPA R’s
- AD effects blocked by rapamycin
- the AD effects of ketamine may due to a primary metabolite, hydroxynorketamine [(2R,6R)-HNK)]
*blocking NMDA receptors —> enhanced Glu function at AMPA receptors —> activate protein kinase mTOR —> changes in synaptic plasticity
Proposed mechanism of ketamine action as an antidepressant
A) selective antagonism of NMDA-R B) antagonism of NR2B-containing NMDA-R C) NMDA-R antagonism leading to BDNF expression D) HNK metabolites E) inhibition of habenula
Prefrontal spinogenesis is required for […]— but not […]— ketamine’s effects on behavior and circuit function
Prefrontal spinogenesis is required for sustaining— but not inducing— ketamine’s effects on behavior and circuit function
Synaptic remodeling in the PFC mediates the transition between depressive behavior and recovery
Stress induces, and KET rescues, clustered spine loss in mPFC and loss of ensemble activity (functional connectivity) in mPFC microcircuits
- mPFC spinogenesis mediates transition between depressive state, remission, and spontaneous recurrence of illness
Newly formed spines are no critical for behavioral recovery, but are necessary for the sustaining KET’s AD effects over time
- KET’s AD effects occur rapidly, before new spine formation suggesting spinogenesis is an activity-dependent adaptation to changes in circuit function
Mechanisms likely involve BDNF/mTOR signaling in mPFC
AMPA agonist action may explain increased neural activity in:
Anterior cingulate cortex
- predicts antidepressant response to ketamine
KET can bind to MOR
Increases BDNF
Tianeptine
TCA structure that modulates Glu function
- GluR1 potentiates AMPA-R function
Ketamine is exciting new advancement in the development of faster and more effective AD’s
IV ketamine produces a rapid, but transient AD effect in animals and humans
- mechanism is not well-defined but likely to involve restoration of stress-induced dysfunction of mPFC
Ketamine is not an ideal therapy
- clinical utility is limited by abuse potential (DEA schedule III drug) and dissociative properties
Natural substances that may have AD properties
Omega- 3 fatty acids
Folate
St. John’s Wort
Omega-3 Fatty Acids
- found in fatty fish (salmon, mackerel)
- efficacy is weak, side-effects are minimal, neuroprotective
Folate
- Vitamin B9, enhances synthesis 5-HT, DA, NE
- Deficient folate metabolism may increase MDD risk
- Few clinical trials, data are equivocal
St. John’s Wort
- Not consistently effective for depression
- Risk? Of serotonin syndrome
- Liver enzyme induction
In bipolar disorder, chronic […] is known to reduce […] function
In bipolar disorder, chronic lithium is known to reduce VTA function
- decreased manic-like behaviors
- lithium carbonate is used to treat bipolar disorder because it enhances 5-HT activity
Drugs for bipolar disorder
- Anticonvulsants: carbamazepine (Tegretol) and valproate (Depakote)
- valproate is used for acute mania
- carbamazepine resembles TCA and can block NE reuptake
- acutely blocks adenosine receptors and up-regulates them with chronic use
- Newer drugs: topiramate (Topamax) and tiagabine (Gabitril)
