Antidepressants and Mood Stabilizers - Craviso Flashcards
Currently available drugs are based on which hypothesis of depression?
The monoamine hypothesis.
Describe the therapeutic strategy and down sides of currently available drugs used to treat depression.
- alleviate depression by affecting monoamine systems
- all cause immediate effects on synaptic monoamine levels
- there is a delay of one or more weeks for symptoms of depression to be alleviated due to later affects
- no one class is superior to the others in treating depression
- at least 20% of all depressed patients are refractory to multiple different antidepressants at adequate doses
Why is there a delay of one or more weeks in relieving symptoms of depression using currently available drugs?
Late effects of these drugs cause a delay due to a slow increase in expression of BDNF that promotes synaptogenesis.
What are the major classes of antidepressant drugs?
- SSRI’s - actions confined to blocking 5HT reuptake
- Serotonin-NE reuptake inhibitors - newer inhibitors selectively block NE and 5-HT reuptake, older inhibitors called tricyclics exert antagonist effects on a variety of receptors (cause more adverse effects)
- New antidepressants - work by various mechanisms including inhibition of dopamine reuptake and agonist/antagonist activities at certain types of 5-HT and NE receptors
- Monoamine oxidase inhibitors - inhibit the metabolism of NE and 5-HT
What are the first line drugs for treating depression?
- SSRI’s
2. selective serotonin-NE reuptake inhibitors - Venlafaxine
In general antidepressant drug actions include what?
- blockage of reupake of serotonin or NE at the nerve terminal
- blockage of metabolism of 5-HT and NE in the nerve terminal
- affect 5HT and NE receptors at the post -synaptic membrane
List the SSRI’s.
- Fluoxetine - prozac, prozac weekly
- Sertraline - zoloft
- Paroxetine - Paxil
- Citalopram - Lexapro
SSRI’s are selective serotonin reuptake inhibitors
What are some important pharmacokinetic considerations when using SSRI’s?
- metabolism occurs in the liver by cytochrome P-450 enzymes
- these drugs may be potent inhibitors of several cytochrome P-450 enzymes - especially CYP2D6
- if CYP2D6 is blocked then the drugs it normally metabolizes could build up and cause adverse effects
Which 2 SSRI’s have a high potential for inhibiting CYP2D6 and other cytochrome P450’s?
Fluoxetine and paroxetine.
Which 2 SSRI’s have a low potential for inhibiting CYP2D6 and other cytochrome P450’s?
Citalopram and escitalopram.
What are the adverse side effects of SSRI’s?
- significant sexual dysfunction such as anorgasmia, ejaculatory delay, impotence and decreased libido
- GI disturbances such as nausea, diarrhea, cramping, heartburn
- insomnia, restlessness
- significant anorexia and weight loss early and significant weight gain long term
- QT prolongation with Citalopram
Describe some other concerns with the use of SSRI’s.
- cause a withdrawal syndrome after long-term use is abruptly stopped - includes nausea, dizziness, anxiety, tremor and palpitations
- use of paroxetine during pregnancy is linked to an increased risk of cardiovascular malformations in the baby
- 5HT syndrome, primarily when used with MAO inhibitors or other drugs that enhance 5HT neurotransmission
What antidepressants can be used for children and adolescents?
Use is limited due to concerns of worsening their depression and suicide.
- Fluoxetine - only SSRI approved for use in children and adolescents
- approved for use in adolescents
Describe some other uses for antidepressants.
- treatment of several types of anxiety disorders
- paroxetine is used to treat seasonal affective disorder
- fluoxetine is used as a migraine prophylactic
- most antidepressants can be used to treat PMS and PMDD
- paroxetine can be used to treat hot flashes
What is Venlafaxine?
A newer, selective serotonin-NE reuptake inhibitor (SRNI). It blocks reuptake of both serotonin and NE and weakly inhibits dopamine reuptake.
What are the adverse side effects of the SNRI’s?
- sexual dysfunction like SSRI’s
- restelessness, insomnia
- GI disturbances like SSRI’s
- dose-related increase in blood pressure
What are the additional uses of SNRI’s
- used to treat anxiety disorders
2. treatment of neuropathic pain
What is Desvenlafaxine (pristiq)?
A metabolite of Venlafaxine
What is Duloxetine (cymbalta)?
- an SNRI
- contraindicated for those with chronic liver disease or hepatic insufficiency
- can be used to treat fibromyalgia, management of diabetic peripheral neuropathy, long term treatment of generalized anxiety disorder
What are Tricyclic Antidepressants?
- SNRI’s
- different TCA’s block both NE and 5HT to varying degrees
- formerly first line drugs to treat depression
List the different TCA’s and to what degree they block uptake of NE and 5HT.
- Nortriptyline (aventyl, pamelor) - blocks NE more than 5HT
- Imipramine (Tofranil) - blocks 5HT more than NE
- Amitriptyline (elavil) - blocks 5HT more than NE
Why are TCA’s not first line drugs anymore?
- can be fatal in overdose
- are cardiotoxic
- have a propensity to lower seizure threshold
- have significant antagonist activity at several types of neurotransmitter receptors - mAch, alpha1, Histamine
Nortriptyline blocks other neurotransmitter receptors - which ones and to what degree?
It blocks mAch, alpha1 and histamine receptors - all to the same degree.
Imipramine blocks other neurotransmitter receptors - which ones and to what degree?
It blocks mAch, alpha 1 and histamine receptors - blocks mAch receptors to a greater degree.
Amitriptyline blocks other neurotransmitter receptors - which ones and to what degree?
It blocks mAch, alpha 1 and histamine receptors - blocks mAch and alpha 1 receptors to a greater degree than histamine but blocks all three to a greater degree than Nortriptyline and Imipramine.
Blocking of mAch receptors causes what?
- sedation
- cognitive impairment
- confusion
- delirium
- blurred vision
- dry mouth
- tachycardia
- urinary retention
Blocking of alpha 1 receptors causes what?
- orthostatic hypotension
2. sedation
Blocking of histamine receptors causes what?
- sedation
At therapeutic doses all of the TCA’s can cause what?
- lowering of seizure threshold
- sexual dysfunction
- weight gain
What are the effects of toxic doses of TCA’s?
- all can cause cardiotoxicity - cardiac conduction delays (QT prolongation), ventricular block, arrhythmias such as Vtach - some patients may even develop cardiotoxicty at therapeutic doses
- acute overdose is often life threatening due to hyperpyrexia, hypertension, and tachycardia, arrhythmias, severe anticholinergic effects and convulsions
What are some drug interactions associated with TCA’s?
- when taken with MAO inhibitors - can cause severe hypertension and risk of 5-HT syndrome
- when tken with anticholinergics and antihistamines - can get additive effects due to blockade of mAch and histamine receptors by TCA’s
- when taken with CNS depressants - can get increased sedation
What is Bupropion (wellbutrin, wellbutrin SR)?
- a dopamine reuptake inhibitor
- can possibly block some of the reuptake of NE and 5HT too
- has fewer sexual side effects compared to other antidepressants
- available in a sustained release formulation called Zyban for use as an aid in smoking cessation
What are the adverse side effects of Bupropion?
- restelessness, insomnia
- anxiety
- risk of seizure activity – dose related
- contraindicated for those with a history of seizures, and eating disorders (electrolyte imbalance)
- may precipitate psychotic episodes in susceptible individuals
What antidepressant has the fewest sexual side effects?
Bupropion - wellbutrin and also Mirtazapine
Excessive dopamine can trigger what?
psychotic episodes
What is Mirtazapine (Remeron)?
- antagonist of central presynaptic alpha-2 adrenergic auto receptors - these mediate negative feedback for NE and 5-HT release
- they also block 5HT2 and 5HT3 receptors
- adverse side effects include sedation, somnolence, dizziness, appetite stimulation and significant weight gain
- similar to Bupropion in that use is not commonly associated with sexual side effects
What is Trazodone (desyrel)?
- blocks 5HT reuptake
- also acts as an antagonist at 5-HT2 receptors and as a partial agonist at 5-HT1A receptors
- adverse side effects include significant drowsiness, dizziness, GI upset such as nausea and vomiting, orthostatic hypotension and possibly priapism
What is Vilazodone (vibryd)?
- is an SSRI and a partial agonist at 5-HT1A receptors
- adverse side effects include insomnia and GI disturbances
- a new drug but has claimed to have no sexual side effects and no weight gain
What is the mechanism of action of the monoamine oxidase inhibitors (MAOI’s)?
Block MAO, the enzyme in nerve terminals that converts the monoamine neurotransmitters such as NE, 5-HT (MAO-A) and dopamine (MAO-B) into inactive products. Helpful in patients who cannot tolerate ow who do not respond to commonly prescribed antidepressants. Have a use in treating Parkinson’s.
Why are MAOI’s considered to be the last choice for antidepressant therapy?
They have a risk of causing hypertensive crisis in response to ingestion of certain foods and drugs.
In what situations can use of MAOI’s cause hypertensive crisis?
If a person is using an MAOI and they eat certain foods such as cheese, salami and red wine that contains tyramine then then there can be a massive release of NE leading to a hypertensive crisis. Tyramine is metabolized by MAOI and if this is blocked it will displace NE in vesicles, causing a massive release of NE.
What is Selegiline (eldepryl)?
- a reversible MAOI
- available as a transdermal system (Ensam) - enables it to bypass the gut, thereby allowing inhibition of central MAO enzymes while reducing the chance of hypertensive reactions caused by tyramine
What is Phenelzine (nardil)?
An irreversible MAOI.
What are the side effects of Selegiline and Phenelzine?
- anorgasmia or sexual impotence
- CNS stimulation - restlessness and insomnia
- sleep disturbances - REM sleep is inhibited
- weight gain
- orthostatic hypotension
- drug reaction when taken with indirect acting sympathomimetics and tyramine containing food
- drug reaction when taken with SSRI’s and 5HT receptor agonists
Manic episodes in Mania and Bipolar are characterized by what?
- exaggerated optimism and self-confidence
- decreased sleep without fatigue
- grandiose delusions and inflated self-importance
- excessive irritability, aggressive behavior
- racing speech, flight of ideas
- impulsiveness, poor judgement
- reckless behavior
What is the general characterization of mood in Bipolar disorder?
Depressive or manic episodes lasting for several weeks to several months often with normal mood in between. Rapid cycling Bipolar is characterized by more than 4 full cycles per year and is rare.
What was/is the first line drug to treat Bipolar?
- Lithium - lithium carbonate (Eskalith-CR), lithium citrate (Cibalith -S)
- Lithium is still in use but the trend is shifting away from its use as a first line drug
- used to treat acute mania, and used as long-term maintenance therapy to avert manic and depressive episodes in patients with Bipolar
- can be used to treat depression in an individual who has a history of bipolar disorder - anti-depressants may trigger mood swings
- can be used during depressive episodes, initially may also need an antidepressant -but use with caution
- not effective for rapid cyclers
What is the MOA of Lithium?
The mechanism of action is unknown but does take several weeks to take effect and involves long term neuroplastic changes.
What are the immediate effects of Lithium?
- inhibition of recycling of inositol (2nd messenger) substrates
- altering the function of G-proteins associated with B-adrenergic and muscarinic Ach receptors
What are the pharmacokinetic considerations when using Lithium?
- distributes in total body water (because its an ion)
- peak plasma levels occur in 1-2 hours with standard preps and in 4 hours with slow release preps
- eliminated in kidney, 20-24 hour half life
- renal clearance is proportional to plasma concentration
- physiologic states associated with decreased renal clearance can cause increased lithium levels
- interferes with sodium reabsorption so may promote sodium depletion - opposite also true - sodium depletion may cause significant lithium retention
What drug-drug interactions should be watched for with the use of lithium?
Can get increased (lessens therapeutic effect) or decreased (may cause toxicity) clearance.
- clearance is decreased by loop and thiazide diuretics, NSAIDs (except aspirin and acetaminophen) and ACE inhibitors via depletion of sodium
- clearance in increased with certain drugs such as osmotic diuretics, acetazolamide, caffeine and theophylline
What are the adverse side effects of Lithium?
At therapeutically effective levels - 0.5-1.5 mEq/L :
- drowsiness, slowed mentation and forgetfulness
- GI disturbance - nausea, vomiting and diarrhea
- polyuria and thirst (decreased response of kidney to ADH)
- weight gain
- mild tremor - principally in fingers
With long term use:
- degenerative changes in the kidney such as interstitial nephritis
- depression of thyroid function (goiter)- due to interference with iodine use in thyroid
Should Lithium be used if a woman is pregnant or breast feeding?
No, it may cause Ebstein’s anomaly (congenital defect in tricuspid valve).
What is a property of Lithium that can lead to issues with its use?
Lithium has a low therapeutic index so serum levels must be carefully monitored - always monitor for conditions that may decrease volume of distribution or renal clearance. Toxicity can be seen at ANY blood levels.
In general, serum levels of lithium above 2.5 mEq/L can lead to what?
- ataxia
- gross tremor
- cardiac arrhythmias
- coma and convulsion and even death
What is Valproic acid (Depakote, depakote ER)?
- an anti epileptic drug that can be used to treat bipolar
- some consider it the first line drug for treating mania and mixed states
- can be more sedating than lithium - but considered safer
- effective in treating rapid cyclers
What is Carbamazepine (tegretol, tegretol XR, equetro)?
Another anti epileptic drug that is used to treat mania and mixed states and that is effective in treating rapid cyclers.
List other FDA approved drugs for treating bipolar.
- Atypical antipsychotics
- Quetiapine - seroquel
- Olanzapine - Zyprexa
- Risperidone - risperdal
- Aripiprazole -abilify
- Lurasidone - latuda - used to treat bipolar depression only
- Asenapine - saphris
- Benzodiazepines - adjuncts in treating acute mania and agitation
- Lorazepam - ativan
- Clonazepam - klonopin
- Lamotrigine - lamictal - new drug used for bipolar depression
