TASK 3

Question 1

Major depressive disorder

Answer 1

Major depressive disorder: chronic, recurring, and potentially life-threatening illness.
- affective disorder characterized by decreased interest in pleasurable activities and the ability to experience pleasure, sleep problems, fatigue, feelings of worthlessness or excessive guilt, thought of death and suicide.
- Often anxiety symptoms co-occur.
- Severe depression can be associated with symptoms of psychosis or loss of touch with reality.
Dysthymia: people with mild but prolonged symptoms that persist for at least 2 years

• 2nd most disabling disease worldwide
• 10% of men and up to 25% of women experience depression in their lifetime
• Only about 21% of patients are adequately treated

Question 2

Tricyclic antidepressants

• types
• pharmacokinetics
• pharmacological effects (side effects, major disadvantages)

Answer 2

first generation antidepressants:

block presynaptic transporter protein receptors for norepinephrine and serotonin.

All drugs have a 3-ring molecular core.

TYPES: Imipramine is the prototype TCA; Desipramine is the inactive intermediate metabolite of imipramine; amitriptyline has an active intermediate metabolite, nortriptyline

Pharmacokinetics:
They are well absorbed when administered orally.
- Half-lives: relatively long (take them at bedtime).
- Peak plasma levels: 2-6 hours after oral administration
- Metabolized in the liver: 2 TCAs are converted into pharmacologically active intermediates that are detoxified later. Therefore the effects can last up to 4 days
- In older patients the effect lasts even longer

PHARMACOLOGICAL EFFECT: elevated mood, increased physical activity, improve appetite & sleep

• side effects:
  a) histamine blockage: drowsiness and sedation
  b) acetylcholine blockage: confusion, memory, cognitive impairment and dry mouth

DISADVANTAGE: slow onset, side effects and FATAL in overdose
- also no more efficacious than SSRI

Question 3

MONOAMINE OXIDASE INHIBITORS (MAOIS)

• pharmacological effect
• side effects
• benefits
• mechanism of action

Answer 3

bind to and block monoamine oxidase, which usually breaks down monoamines (nonspecific effect)
- 3 classic types that form an irreversible bond with enzyme that cannot be broken: enzyme function returns when new enzyme is synthesized (takes 2 weeks)

Pharmacological effect:
- Half-live: nor relevant as they bind irreversibly with MAO – it depends on the synthesis of new MAO

Side effects: : limited by potentially fatal interactions when taken with certain foods and medicines: adrenaline like drugs, cold medicines; tyramine containing food

BENEFITS:

1. they are safer than SSRIs
2. they can work in many patients who respond poorly to both TCAs and SSRIs
3. they are effective drugs for treatment of atypical depression, masked depression, anorexia, bulimia, bipolar depression, panic disorders, phobias, depression in the elderly

Question 4

Heterocyclic/atypical antidepressant

TYPES and benefits & side effect of each type

Answer 4

slight modification of the basic tricyclic structure

1. Maprotiline: Long half-life, blocks norepinephrine reuptake, as efficacious as imipramine. It offers only a few therapeutic advantages = not the first choice in treatment
2. Amoxapine: structurally different from TCAs. Norepinephrine reuptake inhibitor, as effective as imipramine but slightly better at relieving anxiety and agitation.
   - Side effects: parkinsonian like, fatal in overdose
3. Trazodone: as effective as the TCA’s. It is not a potent reuptake blocker of norepinephrine or serotonin
   - Drowsiness: can be taken at bedtime as a sleeping pill: its peak is reached quickly and it declines rapidly, not resulting in tolerance
   - Side effects: can lead to impotence and infertility
4. Clomipramine: structurally a TCA but has a greater effect on serotonin reuptake (mixed serotonin-norepinephrine reuptake inhibitor). It is an effective antidepressant and anxiolytic. Its active metabolite also inhibits norepinephrine reuptake
   - Side effects are qual to TCA’s
   - Used to treat OCD, panic disorder and phobic disorders
5. Burproprion : reuptake inhibitor of dopamine and norepinephrine (NDRIS). Not include serotonin neurons, so it doesn’t have the common side effects of SSRIs.
   - Used to quit smoking, to treat depression
   - Weight loss, anxiety, restlessness, tremor, insomnia, seizures at higher doses
   - Not many drug-drug interactions

Question 5

Selective serotonin reuptake inhibitors (SSRI)

not types or side effects

Answer 5

Potent blockers of presynaptic transporters for serotonin reuptake

• The degree to which they block reuptake of NTM depends on the different drugs: more selectivity of the drug implies a more severe discontinuation syndrome and greater potential to induce serotonin syndrome
• clinical differences between types is minimal
• not fatal in overdose

Question 6

Why do patients not respond to SSRI or respond differently to it?

Answer 6

Patients respond differently to the different types, due to differences in half-lives, receptor selectivity and in effects that inhibit cytochrome P450 drug-metabolizing enzymes in the liver (affect other drugs that are taken by patients), length of treatment

Question 7

Side effects of SSRI

Answer 7

Serotonin syndrome: caused by high doses of SSRIs or serotonergic drugs. It leads to cognitive disturbances, behavioral agitation and restlessness, autonomic nervous system dysfunctions and neuromuscular impairments.
- all drugs that increase serotonin can produce that symptom (additive effects)

SSRI discontinuation syndrome: it occurs in 60% of patients. Less likely when the SSRI had a long half-live. Onset occurs within a few days and it persists 3-4 weeks.
- Flulike symptoms, insomnia, nausea, imbalance, sensory disturbances, hyperarousal

SSRI-induced sexual dysfunction: 80% experience problems with orgasm, loss of libido
-	Stop medication and switch to another class of antidepressants 

Additional side effects: suicidality, sleep disturbance, apathy, physiological symptoms (nausea, headache, lethargy, muscle cramps, seizures, coma and respiratory arrest)

Question 8

Effects of the different serotonin receptors

Answer 8

• 5-HT1A receptors: antidepressant and anxiolytic effects,
• 5-HT2 – insomnia, anxiety, agitation, sexual dysfunction, serotonin syndrome
• 5-HT3 – nausea

Question 9

Types of SSRI

Answer 9

Fluoxetine (prozac): first SSRI: comparable to TCAs with fewer or no anticholinergic or antihistaminic side effects

• used to treat MDD, dysthymia, bulimia, alcohol withdrawal and anxiety disorders
• Half-live: 2-3 days, but its active metabolite lasts for 6-10 days
• Slow onset of effects
• Side effects: anxiety, agitation, insomnia, serotonin syndrome and sexual dysfunction
• active metabolite
• inhibits CYP450 and can lead to drug-drug interactions
• Fluvoxamine: structural derivate from fluoxetine

Sertraline (Zoloft): 4-5x more potent than fluoxetine in blocking serotonin reuptake and is more selective, which leads to more serotonin associated side effects

• steady state:4-7 days
• treat depression, anxiety disorders, dysthymia

Paroxetine (Paxil): it is more selective than fluoxetine in blocking serotonin reuptake.

• Half-life is about 24 hours, steady state is achieved in 7 days
• metabolite is relatively inactive
• Most associated with serotonin syndrome, serotonin discontinuation syndrome, psychosis, paranoid ideations, delusions and even visual hallucinations

Citalopram (Calexa):

• Peak plasma levels in about 4 hours, stead state is achieved in about 1 week and maximal effects in 5-6 weeks
• Half-life: 33 hours

Escilatopram: therapeutically active isomer (mirror-image molecule) of citalopram, but 2x as potent

Vilazodone: SSRI that is a weak stimulant at 5HT1A (no advantage over older agents
- new SSRI

Vortioxetine: several different actions at various serotonin receptor subtypes

Question 10

Dysthymia

Answer 10

mild but prolonged symptoms of depression (2 years)

Question 11

SELECTIVE NOREPINPEHRINE REUPTAKE INHIBITORS (NRI’S):

Answer 11

not effective in treating depression

Question 12

Serotonin-norepinephrine reuptake inhibitors (SNRIs):

Answer 12

Third generation antidepressants

Milnacipran: blocks the reuptake of norepinephrine and serotonin. It blocks NMDA-type glutamate receptors in the spinal cord, contributing to analgesic action
- Used to treat fibromyalgia – reduces chronic pain

Venlafaxine: mixed serotonin-norepinephrine reuptake inhibitor: serotonin blockade occurs at lower doses than does the norepinephrine blockade. At higher doses it also inhibits the reuptake of dopamine

• Lacks antihistaminic and anticholinergic effects; less drug interaction
• Half-life: 5 hours; active metabolite: 11 hours
• Side effects: sexual effects, can trigger manic state, blood pressure elevation
• few drug-drug interactions

Desvenlafaxine: active metabolite of venlafaxine.
- 11-hour half-life

Duloxetine: blockade is more complete than that of venlafaxine.

• Treatment for depression and anxiety, reduce pain
• Half-life 12 hours
• Side effects: nausea is the most common one

Question 13

Mixed Serotonin Antagonist/reuptake inhibitors:

Answer 13

Third generation antidepressant:

Nefazodone: strongest action: 5-HT2 receptor blockade, but it also inhibits serotonin and norepinephrine reuptake
- Can produce liver failures 3-4 x greater than in the general population

Question 14

Noradrenergic and specific serotonergic antidepressants (NaSSAs)

Answer 14

Third generation antidepressant

Mirtazapine: its antidepressant action may be more rapid than that achieved with other antidepressants. It increases the release of both norepinephrine and serotonin by:

1. Blocking central alpha 2 autoreceptors, causing an increase in the release of norepinephrine
2. Blocking adrenergic heteroreceptors located on the terminals of serotonin-releasing neurons, where they normally inhibit the release of serotonin. When they are blocked, 5-HT neurons release more serotonin
3. Increasing release of serotonin stimulates only 5-HT1 receptors, because 2 and 3 type receptors are blocked by mirtazapine (It does not produce the side effects of SSRIs)
   - Side effects: increased appetite, weight gain; it also blocks histamine receptors – drowsiness
   - Half-life: 20-40 hours

Question 15

Efficacy of antidepressant

• Fournier study

Answer 15

only improves depression modesty with treatment
- limited effects on cognitive functions and severe side effects

Fournier study: all kinds of depression severity were taken into account and studies with washout periods were excluded
- they did not want to udnerestimate the high rate of placebo response (usually people who show a response to placebo are taken out during the wash out period)

a) medication vs. placebo differences varied as a function of baseline severity: high baseline severity = antidepressant effects
b) drug effects were non-existent among patients with mild & moderate baseline symptoms

GOLD standard: double blind, placebo-controlled trials

Question 16

Development of new antidepressants

animal trials, models and their limitations

Answer 16

ANIMAL TRIALS:

a) Phase 1: an initial screening for a desired activity
b) Phase 2: more elaborate determination of desired activity and pharmacokinetics
c) Phase 3: a definite judgement of the drugs pharmacology

Behavioral models: Investigators rely on animal models to attempt to reproduce psychiatric pathology. They usually focus on a subset of depression-related behaviors.
- Induce acute or chronic stress to resemble depression

Mechanistic models: The most common tests evaluate antagonist of reserpine. Reserpine depletes monoamine NTM, which leads to depression.

Limitations of these models:
humans and animals are not equal, only able to identify drugs that work through actions on monoamines

Question 17

Selection of antidepressant

Answer 17

1. Assessing the need for intervention: assessing the likely result if pharmacological treatment is not given (risk-benefit assessment)
   a) Longitudinal factors: the course and duration of previous episodes of depression should be considered
   b) Cross sectional factors: the severity of symptoms and the degree pf functional impairment should be considered
2. Assessing the likelihood of success:
   a) Endogenous: primary biological basis
   b) Exogenous: environmental cause

• melancholic depression: include many factors linked to endogenous type of depression and is highly responsive to therapy
• atypical depression: differ due to neurovegetative symptoms – they have hypersomnia, hyperphagia, psychomotor agitation
• poor response predictors: personality features (neurotic, hysteric); multiple prior episodes; delusions; psychomotor agitation
• genetic predictors: the short s allele of the 5HTTLPR promotor may reduce transporter expression and in turn the antidepressant response

Question 18

Formulation of treatment

Answer 18

1. SELECTION OF A PARTICULAR AGENT:
   a) Longitudinal factors: History of response to a particular agent, family history, history of prior side effects and history of symptoms that could suggest mania

b) Cross-sectional factors: Data from the physical examination, which might suggest susceptibilities to certain antidepressant agents or contraindications based on physical illness
- Anxiety is a predictive symptom – do better with sedating antidepressants

GENDER, ETHNIC AND RACIAL ISSUES:

a) Gender: women have a slower gastrointestinal absorption and slower gastric emptying, as well as less volume; smaller livers
b) Race and ethnicity: Asians tend to carry the poor metabolizer trait cytochrome p450 2C19

Question 19

Preparation of patient (info about side effects)

Answer 19

proper education and reassurance about side effects can help reduce nonadherence

Predictable side effects:
- Muscarinic acetylcholine receptors Gastrointestinal effects: decreased salivation and peristalsis (can cause constipation); Blurry vision;
Central nervous effects: impaired memory and cognition
- Histamine H1: sedation; weight gain and orthostatic hypotension; impair motor coordination, cognitive impairment
- Norepinephrine Symptomatic effects: anxiety, tremors, tachycardia
-Dopamine: Anti-parkinsonian effect, psychomotor activation; aggravation of psychosis

Idiopathic effects: Effects that are not well understood:

allergic reactions, liver effects (abnormal liver function), seizures (preexisting seizure disorder increases an antidepressant’s likelihood of precipitating a seizure; family history, brain damage…), precipitin of mania, sexual dysfunction, miscellaneous (fine tremors, excessive sweating, migraine…)

Question 20

Pharmacodynamic interactions vs. pharmacokinetic interactions

Answer 20

1. Pharmacodynamic interactions: propensity of one drug to affect the ability of another drug to bind to its target receptor
2. Pharmacokinetic interactions: ability of one drug to influence the pharmacokinetics (absorption, distribution…) of another drug
   o Can happen through protein binding

Question 21

Initiation of treatment with antidepressants

Answer 21

Choosing a drug:

Elderly patients:
a) Pharmacokinetic concerns: decreased efficiency of metabolizing, decreased muscle fat-ratio: alteration of volume
b) Pharmacodynamic concerns: changes in densities and sensitivities of various receptors
- Elderly patients require lower blood levels of antidepressants is not correct
Efficacy: just as useful as in young adults

Medically ill patients:

• Cardiovascular patients: Depression may adversely affect the prognosis of cardiac
• Poststroke depression: Mixed results
• Cancer: Certain antidepressants may have additional benefits
• Hepatic impairment: Most antidepressants can cause liver abnormalities.

Suicidal patients: concerns about the relationship between antidepressants and suicide
- For subjects that had ever used antidepressant the current use was associated with an increased risk of suicide attempts but a decreased risk of completed suicide

Question 22

Phase of treatment

Answer 22

Treatment can be divided into several phases

1. Early/ preresponse period: The goal is to manage the side effects of various medications: side effects are the primary reason for nonadherence
   - Dose reduction, adjunctive agents or switch of agents
2. Response or acute treatment period: goal is to control acute symptoms of depression
   a) complete response: total recovery from all symptoms
   b) partial response: reduction in symptoms
   - type to response varies in patients
3. Continuation period: Lasts 5-8 months after the end of the acute treatment period
   Goal is the prevention of relapse: if treatment is discontinued in this phase, there is a high risk of relapse

• risk of relapse: high number of previous depressive episodes; underlying dysthymic disorder

4. Discontinuance of treatment: Goal is to enable early intervention should the symptoms recur
   - withdrawal can occur
5. Maintenance period: Goal is to prevent the recurrence of depression
   - long-term therapy can be considered because depression is a lifelong disease
   - seriousness of previous episodes, degree of response to treatments and the ability to tolerate the drug must be taken into account

Question 23

Why does treatment of antidepressants fail?

Answer 23

most often due to inadequate treatment (inadequate length or dose) rather than true non-response
- patients may also have a type of depression that would predict poor responses

Question 24

Treatment augmentation

Answer 24

for a partial response with no signs of continued improvement, treatment augmentation can be of benefi

Question 25

Ketamine effects that can be observed

Answer 25

Effects: mood enhancing, altered physical spatial and temporal states, can lead to hallucinations, out-of-body experiences, amnesia

NMDA receptor antagonist; increase glutamate in the brain

Treatment of depression: produces rapid, transient relief from depression (seen within hours)

EFFECTS THAT CAN BE OBSERVED:

• Leads to reversal of the deficits in synaptic number and function resulting from chronic stress exposure
  1. burst of glutamate and increase and increase in BNDF = increase formation of new synapses
  2. amygdala becomes less responsive
  3. Higher glutamate activity in ACC = important for motivation and cognitive control (depressed patients = low)
  4. less active DMN
  5. less active lateral hebenula: responsible for learning from negative experiences

Question 26

How does ketamine work?

Answer 26

IDEAS ON HOW THIS WORKS:

1. depression = imbalance in glutamate: ketamine may block NTM from binding to NMDA receptor –> no more inhibition of glutamate
   - problem: other agents binding to NMDA receptors failed in clinical trials
2. Ketamine might work through AMPA receptors: a metabolic compound that works similar to ketamine doesn’t work on NMDA receptors but produce rapid antidepressant effects

Question 27

Limitations of ketamine as a treatment

Answer 27

LIMITATIONS: abuse potential, need for intravenous administration, it has not been approved due to its dangerous side effects: learning and perception problems, memory disorder, inflamed bladder

• only taking ketamine to treat depression will not help permanently. It is important to also make a therapy or any other form of treatment
• unclear whether repeated use is safe

Question 28

Esketamine

Answer 28

approved by FDA: nasal spray that works as an NMDA receptor antagonist and has antidepressant effects

Question 29

Monoamine hypothesis of depression

Answer 29

Depression is due to a deficiency of serotonin, norepinephrine and dopamine. Restoring these NTM by prolonging their action was responsible for recovering a normal mood state.

• Weakness: The NTM changes occurred soon after drug administration, but the clinical antidepressant effects develops more slowly (4-6 weeks). Direct evidence is missing.
• Answer: It was hypothesized that this delay was due to changes in receptor sensitivity caused by the chronic increase in synaptic levels of NTM

Question 30

MONOAMINE RECEPTOR HYPOTHESIS AND GENE EXPRESSION

Answer 30

Abnormality in the receptors for monoamine neurotransmitters leads to depression. The depletion of NTM causes compensatory upregulation of postsynaptic NTM receptors.

• Weakness: general evidence is lacking, but postmortem studies show increased number of serotonin 2 receptors in the frontal cortex of patients who commit suicide
• Antidepressants actually downregulate the postsynaptic NTM receptors. The time course of receptor adaptation fits both with the onset of therapeutic effects and with the onset of tolerance to many side effects

Question 31

NEUROGENIC THEORY OF DEPRESSION

Answer 31

Antidepressants alter functions of secondary messengers within a neuron:
protect neurons from damage and healthy neurons

STRESS increases cortisol, leading to a reduction in frontal and hippocampal neurogenesis

CREB activates genes that control the production of brain-derived neurotrophic factor (BNDF), which is important for the normal development and health of the nervous system.
Chronic stress and depression decrease production of BNDF, treatment can increase it again.

– CREB increases in hippocampus during treatment: activates BNDF = neurogenesis
(overactivity of HPA axis and hippocampal shrinkage found in patients)
- therapeutic decay occurs due to time needed for new neurons to develop (monoamines are linked to g-protein, which activates second-messenger functions. alterations of g-protein take time)
- genetic variability in BNDF influences the risk of developing depression

MDD IS CONSIDERED A NEURODEGENERATIVE DISORDER

Question 32

how do the different theories of depression connect?

Answer 32

Depletion of monoamines –>antidepressants –> downregulation of postsynaptic receptors due to increased NTM at the synapse –> alterations in gene expression (increase synthesis of various neurotrophic factors, such as the BNDF)

1. • according to monoamine hypothesis: monoamines are decreased in depressed patients. When giving antidepressants, level increase again
2. • NTM receptor hypothesis: increased levels of monoamine (can explain side effects) lead to a down regulation of serotonin receptors presynaptically and postsynaptically (auto receptors cause them to down regulate) - matches the onset of therapeutic actions
3. monoamines bind to g-proteins, which leads to intracellular changes (increase synthesis of various neurotrophic factors, such as the BNDF)

Question 33

Cognitive neuropsychological approach

Answer 33

Negative affective biases in depression:
Depression is increased following a period of stress and individual differences in how these negative events are experienced and recalled can exacerbate these effects (depressed patients = negative evaluation)

Negative bias might play a role in determining response to everyday social situations, events and stressors and the evolution of depression over time
- effect is reversed when taking antidepressants: a single dose facilitate the recognition of happy facial expressions

Prediction of clinical action: patients who show the greatest resolution of negative bias are more likely to respond to the administered drug with continued administration
- if an early change in positive processing isn’t seen, patients have little chance of responding to the same treatment later

These findings challenge the view that antidepressants do not have an effect until they are administered over time: it might be that nonconscious changes in affect are only apparent to the patient after interaction with the social environment

• mood response after exposure to a stressor is affected
• patients that are nonresponsive to treatment may have long-standing negative affective biases or highly adverse social environments that cannot support an improvement in mood even with remediation of the negative affective bias