Major Affective Disorders - Depression and Bipolar Async

A group of symptoms of worthlessness, guilt, low self esteem, lack of sleep, low energy, aimless, lethargic, loss of pleasure in life (anhedonia), introverted, poor social skills, suicidal thoughts, etc

depression

two types of depression

reactive depression and endogenous depression

causes/risk factors of depression

•Genetic – higher risk if parents have depression

•Biological – reduced levels of neurotransmitters, hormone imbalance

•Environmental - stress, lifestyle, health

•Psychological – childhood trauma, divorce, death of loved ones, financial problems, physical abuse, substance abuse, iatrogenic (medical like drug treatment) etc.

what could be a biological cause of depression?

reduced levels of neurotransmitters

•Debilitating condition that continues for weeks or longer and disrupts life.

•Symptoms include extreme sadness, hopelessness, lack of energy, irritability, trouble concentrating, changes in sleep or eating habits, feelings of guilt, physical pain, and thoughts of death or suicide.

major depressive disorder

major depressive disorder

a mood disorder in which a person feels sad and hopeless for weeks or months

dysthymia

a form of depression that is not severe enough to be diagnosed as major depression

•also called persistent depressive disorder (PDD), involves fewer symptoms than MDD.

•A type of depression that causes a low mood over a long period of time; perhaps for a year or more.

dysthymia

Premenstrual Dysphoric Disorder (PMDD)

depression that affects women during the second half of their menstrual cycles

PMDD vs PMS

- PMDD is more severe and disabling than

PMS

- Greater focus on mood disturbance than

physical symptoms

- PMS affects ~85% of women, while PMDD affects ~5%

characterized by feelings of extreme sadness, fatigue, loneliness, hopelessness, suicidal thoughts, fears about hurting the baby, and feelings of disconnect from the child

Postpartum Depression (PPD)

range of severity (PPD)

Baby blues --> PP depression --> PP psychosis

mental state characterized by delusions and hallucinations, not typically associated with depression

psychosis

People with _______________ may become catatonic (muscular rigidity and mental stupor), stop speaking and refrain from leaving their room.

psychotic depression

treatment psychotic depression

Both an antipsychotic and antidepressant might be used

A subtype of depression involving symptoms of

•Insomnia

•Loss of appetite

•Diminished ability to feel pleasure in positive things/events (anhedonia)

•Intense sadness -life has no meaning or purpose

•Mostly classified as a serious form of depression --> treatment resistant

Melancholic Depression

what disorder is melancholic depression associated with?

bipolar disorder

what form of depression is associated with bipolar disorder?

melancholic

this form of depression can be treated with light therapy and/or antidepressants

SAD

what are some challenges in diagnosing depression?

•Somatic complaints

•Social stigma

•Patient denial

•Associated with other diseases or side effects of other meds

•Absence of lab tests

name the neurotransmitter:

alertness, energy, anxiety, attention --> ?

anxiety, obsessions, compulsions --> ?

attention, motivation, pleasure, reward --> ?

alertness, energy, anxiety, attention --> NE

anxiety, obsessions, compulsions --> 5-HT

attention, motivation, pleasure, reward --> DA

Monoamine Theory

depression is due to decreased norepinephrine or serotonin in the limbic system

Neurotransmitter Dysregulation Theory

depression is due to a persistent impairment and failure to regulate neurotransmitters rather than a simple increase or decrease in neurotransmitter output

Neuroplasticity Theory

depression due to low levels of BDNF preventing growth and connection between neurons

BDNF

Brain derived neurotrophic factor (BDNF) promotes growth of immature neurons and promotes survival of adult neurons

what can affect BDNF levels?

stress

Neuroendocrine Theory

•Dysregulation of the HPA axis results in higher CRF released from the hypothalamus --> higher cortisol

•Dysregulation of HPT axis leads to thyroid hormone deficiency in treatment resistant depression

Neuroinflammation Theory

Dysregulation of the immune system (Cytokine 3) may be associated with the etiology and pathophysiology of depression

how has pharmacological treatment supported the monoamine theory of depression?

Pathologically low levels of monoamine causes depression [Abnormally high levels of monoamine causes mania]

Medications that increase monoamines improved depression [and worsened mania]

what do low levels of monoamine cause? and high?

low: depression

high: mania

what are the limitations of the monoamine theory?

1. L-dopa and tryptophan (direct precursors) do not affect mood

2. Cocaine and amphetamines which block reuptake do not improve mood

3. Lag time: Takes 2 -4 weeks to exert any benefits, even though a boost in monoamines occurs within hours

Imipramine, desipramine, nortriptyline, amitriptyline - examples of? MOA?

Tricyclic antidepressants (TCAs)

Block NE and 5-HT transporter sites on the presynaptic neuron which prevents their neuronal reuptake and increases their concentration and postsynaptic effect

Structurally related to the phenothiazine antipsychotics

Consist of 3 rings; 2 phenyl rings fused to a central 6 or 7 membered ring

Tricyclic antidepressants (TCAs) - Imipramine, desipramine, nortriptyline, amitriptyline

what would inactivate a tricyclic antidepressant?

removal of one of the benzene rings

Fluoxetine, sertraline, paroxetine, citalopram, escitalopram

Selective serotonin reuptake inhibitors (SSRIs)

what structurally makes SSRIs selective for 5-HT?

Halogen substituent on aromatic ring

most prescribed antidepressant class

SSRIs - Fluoxetine, sertraline, paroxetine, citalopram, escitalopram

First FDA approved prototype SSRI (1987), least selective, most widely prescribed, sales exceed $1B/year

Fluoxetine

most selective SSRI for 5-HTT, half life of 35 h

Citalopram

Demethylated active metabolite of Fluoxetine, ______________ has half life of 4-16 days, resulting in considerable drug accumulation

Norfluoxetine

S(+) isomer of (±) Citalopram, high 5- HTT selectivity

Escitalopram

SSRI with highest affinity for 5-HTT, no active metabolites

Paroxetine

SSRI with high plasma protein binding

Sertraline

what happens to amitriptyline in the body and how?

Amitriptyline is metabolized by CYP2C19 to its active metabolite, nortriptyline

what NT does nortriptyline mostly prevent the reuptake of? what can it also block leading to side effects?

NE

Nortriptyline also inhibits Hist, 5-HT and ACh, leading to side effects

Amitriptyline mostly blocks reuptake of __________ while its active metabolite, nortriptyline blocks mostly _____________

5-HT; NE

what CYP metabolizes nortriptyline?

CYP2D6

Nortriptyline black box warning

suicide in adolescents, children, and young adults with MDD and other psychiatric disorders

Duloxetine, venlafaxine, desvenlafaxine

Serotonin norepinephrine reuptake inhibitors (SNRIs)

___________was developed as a selective SNRI but later found to also work as SSRI

Venlafaxine

SNRIs indications

Effective in patients who do not respond to standard antidepressants

Also used for patients with chronic pain (e.g., neuropathic pain, fibromyalgia, musculoskeletal pain)

Bupropion

Norepinephrine and dopamine reuptake inhibitor (NDRI)

what does Bupropion block? which does it block more?

blocks DA reuptake (more) and NE reuptake (less)

Off-label uses include anti-depressant-induced sexual dysfunction, ADHD, depression associated with bipolar disorder, and obesity.

Bupropion

how long does it take for Bupropion to start working?

2 weeks

Bupropion is metabolized in the liver by _____________ to hydroxy-bupropion (active metabolite)

CYP2B6

Bupropion black box warning

suicidal thoughts and behavior in children, adolescents, and young adults

which antidepressant does not cause sexual dysfunction?

Bupropion

Most severe adverse effects of this antidepressant are lowered seizure threshold and the potential of worsening suicidal ideation

Bupropion

Selegiline

Irreversible, MAO B Inhibitor

Trazodone, nefazodone, vilazodone, vortioxetine

Mixed 5-HT modulators

what specific site on the 5-HT receptor sites can be targeted in SSRIs treatment resistant patients

5-HT2A R

5-HT1A R

Upregulation of which 5-HT presynaptic autoreceptor appears to be involved in the pathogenesis of major depression - what can treatment with an agonist of this receptor do over time?

5-HT1A

Long term treatment with a 5-HT1A agonist leads to desensitization of autoreceptors --> removes negative feedback and increases synthesis and release of 5-HT

overactivation of which 5-HT postsynaptic receptor contributes to etiology of depression and anxiety

5-HT2A

Trazodone MOA

5-HT modulator

First antidepressant with dual MOA, prolongs effect of 5-HT by blocking 5-HT receptors and reuptake:

1. SSRI

2. Blocks 5-HT2 (2A and 2C) receptors located on postsynaptic neuron

side effects of this 5-HT modulator include anticholinergic effects (dry mouth), orthostatic hypotension, and QTc prolongation

Trazodone

Vortioxetine MOA

Atypical antidepressant with dual effects to modulate 5-HT neurotransmission

MOA: SSRI and a 5HT1A agonist

-Blocks 5-HT reuptake (SSRI)

-Agonist at 5-HT1A autoreceptors

Mirtazapine MOA

5-HT and alpha 2 Antagonist

–By inhibiting a2 autoreceptors on NE neurons, it enhances NE synthesis and release of NE

–By concurrently blocking a2 heteroreceptors on 5-HT neurons, it facilitates the release of 5-HT

what are the 4 classes of reuptake (transporter) Inhibitors?

1. Tricyclic antidepressants (TCAs) - first generation antidepressants

2. Selective serotonin reuptake inhibitors (SSRIs)

3. Selective norepinephrine reuptake inhibitors (SNRIs)

4. Norepinephrine and dopamine reuptake inhibitors (NDRI)

what are the downsides to Tricyclic antidepressants (TCAs) ?

•Not selective

•Block other receptors (histamine, cholinergic, etc.)

•Results in many side effects

role of a2 autoreceptors & heteroreceptors in treatment of depression

The similarity between the synaptic mechanisms controlling 5-HT and NE transmission stimulated research into the role of presynaptic a2 autoreceptors in augmenting NE reuptake effects

Use of a2 R antagonist enhances therapeutic effect of NE reuptake blockers

By blocking a2 heteroreceptors located on 5-HT neurons, can also increase 5-HT release

MOAI MOA in depression treatment

MAOIs inhibit MAO enzyme, resulting in an increase in 5-HT, NE and DA in presynaptic neuron --> long lasting effects

1st MAOI antidepressant approved by FDA as a transdermal delivery system for MDD

Selegiline

adverse effects of this antidepressant include sudden sleep episodes, orthostatic hypotension, arrhythmias, mental status alteration, hallucinations, extrapyramidal symptoms, dyskinesia, and serotonin syndrome

Selegiline

Ketamine/Esketamine MOA

NMDA receptor antagonist

which antidepressant is available as a nasal spray?

Ketamine/Esketamine

what can Buproprion be formulated with for increased efficacy? what is that drug's MOA?

Dextromethorphan: Non-competitive antagonist at NMDA receptors

However, has other binding sites and other effects

what is Psilocybin?

Psilocybin is a 5-HT receptor agonist found naturally in some mushroom species (magic mushroom)

Prodrug with phosphate group. Dephosphorylation gives the drug.

Recent studies have assessed the therapeutic potential of psilocybin for anxiety, OCD, smoking and alcohol dependence, with promising preliminary results

Episodes of mood swings from depressive lows to manic highs

BPD

what is a major challenge in the treatment of bipolar disorder?

the development of effective drugs with low toxicity for the patients

what is Bipolar I disorder?

has at least one manic episode in life

lasts for a few weeks to few months

what is Bipolar II disorder?

milder mania + depression

moods cycle between high and low

"up" moods do not reach full blown mania

hypomania

less severe manic phases

Cyclothymic disorder

frequent but brief periods of mood swings, hypomania and depression

can happen spontaneously even within the same day

Mixed mania

Symptoms of mania and depressive episodes are present at the same time

People who experience mixed states describe feeling activated and "revved up," but also feel anguish and despair.

Uncontrollable mood swings can occur over minutes

people with this condition describe feeling activated and "revved up," but also feel anguish and despair

mixed mania

In ______________, a person can experience 4 or more episodes of mania or depression in one year.

rapid cycling

a pattern of frequent, distinct episodes

rapid cycling

what does Lithium treat? MOA?

acute bipolar mania

unknown MOA

Various hypotheses exist for lithium response --> regulating cell membrane properties, cell membrane transport, ion distribution, neurotransmitter regulation, and intracellular signaling

why do most BD patients not respond well to lithium monotherapy?

narrow therapeutic index, poor tolerability, especially at higher doses, and risk of "rebound mania" on withdrawal

common side effects include tremor, polydipsia, polyuria, and long-term treatment can lead to hypothyroidism

long term treatment with lithium can lead to?

hypothyroidism

what is the active species of Lithium salts? how might this affect its MOA?

Li+

-Resembles Na+, can occupy Na+ pump

•Cannot maintain membrane potentials, may prevent release of neurotransmitters (e.g. dopamine) that characterize manic state

activity of this molecule is linked to G proteins and second messenger Inositol triphosphate

Li+

are there animal models that can be used for BPD research?

there are no universally accepted animal models in bipolar disorder and no model can exhibit the characteristic mood swings

how do anticonvulsants act as mood stabilizers?

by making the nerve cells less excitable

Carbamazepine, oxcarbazepine, lamotrigine, valproic acid MOA (BPD)

Blockade of voltage-gated Na+ channels --> prolongs Na+ channel inactivation

Preventing Na+ influx leads to lowering of glutamate mediated excitation

Results in lowering neuronal excitability

Multiple MOAs for Valproic acid

1. Blockade of voltage-gated Na+ channels --> prolongs Na+ channel inactivation

2. Reduces cell permeability to voltage-dependent Ca++ T-type channels

3. Increases brain levels of GABA by inhibiting GABA transaminase

atypical antipsychotics indications

as add-on treatment (with mood stabilizers and antidepressant drugs) and sometimes as monotherapy in treatment-resistant bipolar patients

for short or long-term treatment of bipolar disorder to control psychotic symptoms such as hallucinations, delusions, or mania symptoms

pros and cons atypical antipsychotic medications

pros: less extrapyramidal symptoms (movement disorder) and less risk of tardive dyskinesia

cons: can cause weight gain (olanzapine and clozapine), sedation, and agranulocytosis (clozapine)

structural analog of clozapine with similar pharmacological properties

antagonist at 5-HT2A and DA2 Rs

Olanzapine