PC7 Module 4 (Depression and Bipolar)

What are the three main types of affective disorders?

depression, anxiety disorder, and bipolar disorder

What is the average age of onset for depression?

32 years old

Which is more likely to experience depression? Women or men?

Women (they experience depression at twice the rate of men)

True or False: The etiology of depressive disorders are fully understood and can be explained by any single social, developmental, or biologic theory

FALSE: The etiology of depressive disorders is NOT fully understood and CANNOT be explained by any single social, developmental, or biologic theory

The symptoms reported by patients with major depression suggest changes in which brain monoamine neurotramsmitters?

serotonin (5-HT), norepinephrine (NE), and to some extend dopamine (DA)

True or False: MDD often co-occurs with other medical conditions

True: These patients are typically prone to polypharmacy and hence increased risk of drug-drug interactions

What is the leading cause of disability in the US for ages 15-44 years old AND the leading cause of disability worldwide?

Major depression disorder

Who is more likely to commit suicide? Women or Men?

Males (4X more likely to commit suicide than females)

Finish the term: In order to be diagnosed with MDD, you must have you must have either depressed mood or markedly low interest/pleasure in most activities AND 4 or more of the following:

appetite/weight changes, sleep changes, psychomotor changes, fatigue/anergia, feelings of worthlessness, increased inappropriate guilt, poor concentration, indecisive, suicidal thoughts, plans, or attempts

What does the depressive symptom pneumonic "SIG E CAPS" stand for?

sleep disturbance

interest (decreased)

guilt (increased)

energy (decreased)

concentration (decreased)

appetite (increased/decreased)

psychomotor (increased/decreased)

suicidal thoughts

What is typically the cause of relapse in depression?

the premature stopping of treatment

There is a great degree of overlap in the underlying neurobiology/pathophysiology of which two disorders?

depression and anxiety

True or False: Medications which treat depression can often treat anxiety as well

True: due to their overlap in underlying neurobiology/pathophysiology

What are some infectious diseases that can cause depression symptoms?

tertiary syphilis, influenza, AIDS, viral pneumonia, viral hepatitis, mononucleosis, tuberculosis

What are some endocrine disorders that can cause depression symptoms?

hypo and hyperthyroidism, hyperparathyroidism, menses-related, postpartum, Cushing's disease, Addison's disease

What are some immunological causes of depression symptoms?

systemic lupus erythematosus, rheumatoid arthritis

What are some neurological disorders that can cause depression symptoms?

multiple sclerosis, PD, head trauma, temporal lobe seizures, cerebral tumors, stroke, dementing diseases in early stages, sleep apnea

What are some of the nutritional deficiencies that can cause depression symptoms?

Vitamin B12, C, folate, niacin, and thiamine deficiencies

True or false: There are known reliable biological markers of depression

False: there are no known reliable biological markers of depression

What is the biogenic amine hypothesis?

Major depression disorder results from a lack of one or more of the biogenic amines 5-HT, NE, DA (current theory favors NE and 5-HT)

Although the reuptake blockade of monoamines occurs almost immediately upon initiating an antidepressant the clinical effects generally delayed by how long?

weeks

What is theorized about the reason for the delay in clinical effects?

it may be the result of a cascade of events ensuing from receptor occupancy to gene transcription or changes in receptor sensitivity

How long does it take for antidepressants to have a synaptic effect?

within minutes to hours

How long does it take antidepressants to cause side effects?

within hours to days

How long does it take antidepressants to have therapeutic effects?

generally, a minimum of 4 weeks no matter the antidepressant used

True or False: no antidepressants has shown consistent superiority over another

True

All antidepressants can be expected to take a minimum of how many weeks to exert their full therapeutic effects?

a minimum of 4 weeks

What is bipolar disorder?

a cyclic mood disorder characterized by recurrent and significant fluctuations in mood, energy, and behavior

How does bipolar disorder differ from major depression?

in bipolar disorder, patients have manic, hypomanic, or mixed episodes occur during the course of the illness

What is the criteria for bipolar I disorder?

one or more manic or mixed episodes that fully meet the criteria for mania, and DOES NOT require depressive episodes

What is the criteria for bipolar II disorder?

one or more depressive episodes of at least 4 months duration AND one hypomanic episode

What is "mixed" episodes?

refers to the presence of both high and low symptoms (manic and major depressive episode) occurring at the same time or as part of a single episode nearly every day for at least a one week period

Bipolar I disorder occurs more in which? Males or females?

it occurs equally in both males and females

Bipolar II disorder occurs more in which? Males or females?

more common in females

Comorbidity of substance abuse is common in which psych disorder?

Bipolar

What does the manic episode pneumonic "DIGFAST" stand for?

distractibility

indiscretion (pleasurable activities)

grandiosity

flight of ideas

activity increase

sleep deficit (decreased need)

talkativeness (pressured speech)

What is the difference in social or occupational functioning in a manic state vs a hypomanic state?

In mania, there is a severe impairment of social or occupational functioning, while in hypomania there is no impairment

How long does mania last?

at least 7 days

How long does hypomania last?

no more than 4 days

Which has psychotic features? Mania or hypomania?

Mania has psychotic features, while hypomania does not

Insomnia is likely found in which manic state?

Mania, while hypomania is characterized by diminished sleep

Which manic state would require hospitalization?

Mania

Which manic state would you be worried about aggression/suicidality?

Mania

Which symptom of bipolar disorder is experienced longer than the rest?

Depressive symptoms are experienced longer than manic, mixed, and rapid-cycling symptoms

Which takes longer to recovery? depressive or manic episodes?

Depressive episodes

What is rapid cycling?

greater than four mood episodes within 12 months

What are the major targets for antidepressants?

monoamine transporters, monoamine receptors, monoamine oxidases

Fluoxetine gets metabolized into what active metabolite?

Norfluoxetine

Why has norfluoxetine not been developed as a stand alone drug if it has 20x more potency?

Increased risk of cardiac side effects

What antidepressant has the least effect on cytochrome P450 system therefore have the most favorable profile regarding DDI?

Citalopram and Escitalopram

What is one of the most widely used antidepressant therapies?

Escitalopram

Which SSRI is MOST selective?

Citalopram

Which SSRI is LEAST selective?

Fluoxetine

What are some general features of SNRIs compared to SSRIs?

SNRIs have slightly greater efficacy and fewer adverse effects than SSRIs (not always and not for every patient)

How would you describe TCAs affinity to lipids/fat?

TCAs are EXTREMELY lipophilic

Maximum activity is achieve for TCAs when there are how many carbons in the side chain at the N-5?

2-3 carbons

What is essential to the TCAs SAR?

the basic nitrogen at the end of the chain

What is the largest substituent you can have on the basic nitrogen?

The substituent can be no larger than a CH3

2° amines are ____ active and have a more ____ onset of activity than dimethylamines

MORE and RAPID

What do tertiary amine TCAs block?

they block the uptake of both NE and 5-HT

What do secondary amine TCAs block?

they preferentially block the uptake of NE

What is the general SAR of 5-HT1A receptor agonist?

1) aryl portion (usually phenyl or heteroaryl)

2) intact piperazine ring (optimal for binding 5-HT1A)

3) spacer of 2-5 atoms (length can influence affinity and selectivity)

4) terminus (amide or imide and tolerated bulky functional groups)

What happens to the SAR of beta-adrenergic agonist (isoproterenol) undergoes dichloro replacement (dichloroisoproterenol)?

it becomes an antagonist

Why did pronethaol not go to market? (pronethaol became dicholoroisoproterenol via naphtyl replacement)

withdrawn due to tumor induction in vivo

What happens to the SAR of pronethaol when a oxymethylene bridge is added to the structure?

it creates propranolol a classic beta blocker

Depression is conceptualized as a disorder of?

synaptic plasticity leading to a maladaptive emotional learning

What do individuals with a genetic predisposition for depression have?

negative affective bias

what factor can lead to enduring and profound changes in synaptic plasticity?

chronic inescapable stress

what do the changes in synaptic plasticity gradually lead to?

modifying the shape and connectivity of neurons in key brain regions

The faulty learning process that reinforces the patient can be at least partially reversed by what?

psychotherapy

The emotional impact of stress is greatly influenced by which monoamines?

Serotonin and norepinephrine

Changes in monoamines plus chronic impact of stress leads to alteration in what?

BDNF and other neurotrophic factors which leads to changes in synaptic plasticity

What explains therapeutic lag of antidepressants?

The fact that changes in serotonin and norepinephrine lead to a remodeling of the dendritic arbor of neurons

Where are serotonergic cell bodies mainly located?

raphe nuclei

How many type of serotonin receptors are there?

13

What transporter does serotonin undergo uptake by?

SERT

Serotonin is metabolized by what enzyme?

MAO A

Where are norepinephrinergic cell bodies located?

locus coeruleus

How many norepinephrine receptors are there?

5

norepinephrine undergoes uptake by what transporter?

NET

norepinephrine is metabolized by what enzyme?

MAO A

What is the importance of brain-derived neurotrophic factor (BDNF)

it is involved in cell health or growth as well as cell death in an activity-dependent manner

BDNF are critical for what?

growth and function of the nervous system as well as learning and memory

How is BDNF expressed?

throughout the brain in neurons and glia

The synthesis and release of BDNF is rapidly facilitated by what neurotransmitter?

glutamate

The synthesis and release of BDNF is slowly facilitated by what neurotransmitter?

monoamines

what are the acute effects of cortisol in the CNS?

cortisol increases the release of glutamate and induce other modifications aimed at rapid adaptation to stress

what are the chronic effects of cortisol in the CNS?

cortisol reduces serotonin, norepinephrine, and BDNF resulting in synaptic changes and dendritic remodeling

What effect does depression have on the HPA axis?

it is continuously activated therefore, CRH, ACTH, and cortisol are consistently over-secreted (this can lead to other comorbid illnesses)

What is hypercortisolemia associated with?

neurotoxicity and reduced synaptic formation in certain regions

Excess in cortisol has what effect on BDNF?

BDNF suppression and atrophy of the cortex

In depressed patients, how do systemic and cortical levels of BDNF look?

there is a decrease in both levels of BDNF

How do antidepressants change BDNF levels?

they increase BDNF levels

What is the mechanism of action based on for classical pharmacological treatments for depression?

chronic increase of extracellular monoamine levels

What happens during the acute (hours to days) phase of neurochemical changes for treatment of depression?

rapid increase in monoamine levels and activation of receptors (this is when patients experience side effects)

What happens during the chronic (weeks to months) phase of neurochemical changes for treatment of depression?

decrease in number/activity of pre/postsynaptic receptors for 5-HT and NE but no desensitization of transporter and therapeutic effects with reduction of some side effect due to the stabilization of neurotransmission

What are the transporters that mediate the reuptake of monoamine neurotransmitters?

SERT, NET, and DAT

What happens with chronic blockage of monoamine transporters?

it enhances the synaptic and extracellular levels of monoamines producing antidepressant effects

what is the most commonly prescribed antidepressants?

SSRIs

The adverse events of which drug class are more manageable compared to non-selective antidepressants?

SSRIs