Pharm - Drugs for Mood Disorders

Question 1

Major Depressive Disorder, Dysthymia, Bipolar Disorder

Answer 1

MDD –> Tends to be recurrent, presents more commonly in WOMEN (but may be reporting erro) and does NOT INVOLVE MANIA OR HYPOMANIA

Dysthymia – Less severe than depression, but is still a depressive disorder that NEVER REMITS and can last for YEARS ON END

Bipolar Disorders - Treated extremely differently and include both periods of depression and mania/hypomania

Question 2

How many patients with an affective disorder attempt suicide?

Answer 2

15%

Question 3

What is the biogenic amine hypothesis?

Answer 3

Specific neurotransmitters play a role in depression –> NE, DA, 5HT

The hypothesis argues that low levels of NT (specifically NE, DA, 5HT) activity result in the DEPRESSED MENTAL STATES seen in MDD

Reducing the release of these chemicals may cause depression, and further enforce the chemical basis of the hypothesis

Also a strong genetic component

Question 4

Serotonin Review

Answer 4

Produced by cell bodies in the MIDBRAIN (RAPHAE NUCLEI) that project into almost every part of the cortex and basal ganglia

5HT is diffusely distributed throughout the brain, and excites these areas.

Question 5

Norepinephrine Review

Answer 5

Generated in neurons within cell bodies of the LOCUS COERULEUSS – this is also a diffusely released NT that gets to most areas of the brain

Question 6

Dopamine Review

Answer 6

Much more LIMITED in its distribution –> only really reacts within the LIMBIC SYSTEM and the BASAL GANGLIA to affect motor coordination and the reward systems

Question 7

Production and release of Serotonin?

Answer 7

TRYPTOPHAN - consumed in the diet –> enters neurons and is transformed to 5-hydroxytryptamine (5HT) –> stored in vesicles that respond to depolarization-dependent calcium influx, fuse with the nerve membrane and is then released into the synaptic cleft

The 5HT then binds with any number of receptors (14 overall - 1a and 2a seem most implicated) to cause post-synaptic depolarization

Removed from the synapse b Na/K/Cl ATPase reuptake pumps that are selective for 5HT, but otherwise identical to NE reuptake pumps

NE is the exact same way, just with different intermediaries

Question 8

Selective Serotonin Reuptake Inhibitors Overview

Answer 8

Highly selective reuptake inhibitors

Increase the concentrations of NT in the synaptic cleft of 5-HT synapses to ameliorate some of the symptoms of depression

Typically take 4-12 WEEKS TO SHOW AN EFFECT and there is a LARGE PLACEBO EFFECT for each

Much lower side effect profiles than TRICYCLIC ANTIDEPRESSANTS

As a result, they are a MAINSTAY OF DEPRESSION TREATMENT and have been for 30 years –> these aren’t necessarily better drugs, but they are FAR better tolerated, which leads to better compliance and better outcomes

Question 9

What makes SSRI more effective?

Answer 9

Combining with PSYCHOTHERAPY!!!

Question 10

What is the only anti-depressant that can show abuse symptoms?

Answer 10

BUPROPRION – has activity for NE as well as DA reuptake

Because of blocking the DA, it may interfere with reward pathways leading to abuse!!! (Like the article for SDL #5 said!)

Note: this is NOT an SSRI

Question 11

Why does it take so long to see an effect?

Answer 11

There is a relatively QUICK onset, so why would it take long?

The axons of 5HT neurons that project to the forebrain have RECURRENT COLLATERAL PROJECTIONS that synapse with its own cell body

Serotonin 1a Receptors - INHIBITORY G PROTEIN RECEPTORS - fill the synapse

Just like all synapses, there are also reuptake pumps

If you BLOCK the pumps, there is excess 5HT and this is true at these inhibitory pumps too!!! OVER INHIBITS! REDUCES CELL FIRING!!!!!!

Even though the 5HT remains at the target synapses for longer periods, then neurons themselves ARE NOT FIRING AT HIGH RATES

Overall, the release of 5HT is lowered (ACUTELY)

This accounts for the initial DEEPENING of depression that is first observed when prescribing SSRI

Question 12

So, how do we overcome this autoinhibition?

Answer 12

After long periods of stimulation, the 5HT 1a receptors DOWN REGULATE due to over stimulation!

This results in a RETURN TO NORMAL FIRING RATES OF THE NEURON

Meanwhile, the blockade of 5HT reuptake remains strong in the target synapse!

Thus, SEVERAL WEEKS AFTER STARTING SSRI THERAPY, 5HT levels at the target synapse will INCREASE (more firing of the formerly inhibited neurons!), resulting in the POSITIVE THERAPEUTIC EFFECTS

Question 13

Adolescents and SSRI?

Answer 13

Adolescents are more at risk for suicide, so SSRI ARE NOT APPROVED FOR YOUNG PEOPLE DUE TO THAT INITIAL DEEPENING!!!!

Question 14

What is the ONLY SSRI approved for children?

Answer 14

FLUOXETINE!

Question 15

Is the delay between therapeutic effects limited to SSRI?

Answer 15

NO!

This happens with SNRI and TCAs too!

All anti-depressants therefore have ESSENTIALLY EQUAL EFFICACY AND DELAY IN CLINICAL EFFECT

Question 16

Pharmacokinetics of SSRI

Answer 16

All have VERY LONG HALF LIVES and thus take several days/weeks to REACH STEADY STATE in the body

Stopping or switching these medications needs to be taken seriously and slowly, over the course of a few weeks!

Question 17

FLUOXETINE

Answer 17

Has a half life of 4-6 DAYS!

LONGEST OF THE SSRI –> Since we allow 4 half lives for drug clearance, it means that it is about 4 WEEKS for FLUOXETINE – as a result, it takes a long time to reach steady state and thus a longer time to see therapeutic benefit!

Question 18

What are other SSRI (names)

Answer 18

SERTRALINE (zoloft)
CITALOPRAM
FLUVOXAMIDE

Question 19

Side effects of SSRI?

Answer 19

When taken alone, SSRI are NOT FATAL in overdose

But, as with ANY antidepressant, activity shifts before mood does –> this can be bad –> more active, still depressed –> MAY result in more suicide (again, only Fluoxetine for kids)

Acute Side Effects –> ANXIETY, SLEEP DISTURBANCE, AGITATION; some LOSS OF LIBIDO (> 30%); weight GAIN (but NOT AS MUCH because they DONT block histamine receptors which is commonly associated with gaining weight)

Taper when coming OFF the medication (for a month) due to concerns of WITHDRAWAL

There are NO CARDIAC SIDE EFFECTS (like TCAs!) – they don’t block Na, K or Ca ions in heart tissues, so NOT associated with arrhythmias

These drugs also do NOT block adrenergic or muscarinic receptors, so they don’t interrupt the normal autonomics

Question 20

What is the most important thing to consider with SSRI and drug interactions?

Answer 20

SEROTONIN SYNDROME

Fever, sweating, HTN, anxiety, seizures, hyperreflexia and coma –> leading to DEATH

Question 21

Drug Interactions

Answer 21

Again, can cause SEROTONIN SYNDROME if the drug increases the SSRI concentration

OTHER ANTIDEPRESSANTS (TCAs, SNRI)
**MAO INHIBITORS**
TRIPTANS
DEXTROMETHORPHAN (OTC cough suppressant)
MEPERIDINE/DEMEROL
ST JOHN'S WORT (herbal)

Also, even MODERATE amounts of alcohol can lead to COMA

SSRI are all HIGHLY PROTEIN BOUND (90%), and therefore they COMPETE AVIDLY FOR BLOOD PROTEIN BINDING SITES which can lead to higher levels of other drugs!!!!!

Question 22

SEROTONIN NOREPINEPHRINE REUPTAKE INHIBITORS

Answer 22

Inhibit reuptake of BOTH 5HT and NE so they resemble older TCAs, but DON’T prduce the same side effects (no heart effects!)

These drugs have NOT been shown to be any better than SSRI and carry the same precautions (with interactions, etc)

Question 23

VENLAFAXINE

Answer 23

Inhibits 5HT > NE reuptake, but at therapeutic doses, BOTH ARE INHIBITED

Question 24

DULOXETINE

Answer 24

Inhibits 5HT more potently than NE reuptake, but it’s metabolite DESVENLAFAXINE inhibits BOTH and is available for prescription!!!!

Question 25

Non-SSRI/SNRI --> BUPROPRION

Answer 25

This is a drug that INHIBITS DA and NE REUPTAKE but probably NOT 5HT It is a STIMULANT --> only antidepressant with SIGNIFICANT DA effects --> sold as WELLBUTRIN for depression and ZYBAN for smoking cessation!!!! Side effect profile compares favorably to SSRI --> NO DECREASED LIBIDO (heavily advertised claim; sometimes used WITH SSRI because of this) Implications of stimulant activity? Could cause BEHAVIORAL ACTIVATION (lots of NE and DA) --> insomnia, decreased appetite, agitation --> especially in the EARLY stages --> good to avoid evening doses Also implicated in ABUSE (only anti-depressant)

Question 26

TRICYCLIC ANTI-DEPRESSANTS OVERVIEW

Answer 26

These drugs block THREE NT RECEPTORS --> ACh, HISTAMINE, and NE!!!! In general, these drugs are MUCH LESS POPULAR than SSRI (side effects)

Question 27

DESIPRAMINE

Answer 27

Strong, very specific norepinephrine reuptake inhibitor --> STILL USED TODAY because of its specificity

Question 28

AMITRIPTYLINE

Answer 28

May be used to treat ***NEUROPATHIC PAIN*** as well as depression Diabetic neuropathy, other nerve injuries Not nearly specific like Desipramine

Question 29

SIDE EFFECTS OF TCAs

Answer 29

Increased CARDIAC EXCITABILITY AND ARRHYTHMIAS (block Na, K channels in heart), HTN (beta block), DRY MOUTH (muscarinic block), GI disturbances (muscarinic), MEMORY dysfunction (muscarinic), WEIGHT GAIN (histamine), ORTHOSTATIC HYPOTENSION (alpha adrenergic) While the therapeutic effect takes WEEKS, THESE SIDE EFFECTS OCCUR VERY QUICKLY, which is why there is such a big issue with compliance Don't use in patients with known cardiac abnormalities, or those who have had heart attacks within a year of administration!!!!!

Question 30

TCAs and OVERDOSE

Answer 30

These drugs can be FATAL IN OVERDOSE and have been used for suicide! They are HIGHLY and TIGHTLY BOUND to plasma proteins, so it is DIFFICULT TO REMOVE FROM THE BLOODSTREAM AFTER OVERDOSE Recommended that NO MORE THAN 2 WEEK SUPPLY of TCAs be prescribed until we KNOW the patient and TRUST their ability and willingness to follow directions properly!

Question 31

What is the only drug that has any effect of DA again?

Answer 31

BUPROPRION!

Question 32

MAO INHIBITORS

Answer 32

These drugs DECREASE METABOLISM of NE, 5HT and DA thus INCREASING their concentrations at the synaptic terminals --> this ALSO increases release by REVERSING THE REUPTAKE PUMPS! This can be highly problematic because of the NUMEROUS INTERACTIONS with other drugs and even TYRAMINE CONTAINING FOODS (too much tyramine - not broken down when MAO is inhibited - will DISPLACE NE, causing it's release, and HYPERTENSIVE CRISIS!) PHENELZINE, TRANYLCYPROMINE, CHLORGYLINE are all indicated for depression (don't need to know names) Deprenyl is a MAO-B inhibitor approved as an adjunct for PD Remember - combinations of MAOI, TCA or SSRI can CAUSE SEROTONIN SYNDROME! Not widely used today

Question 33

What is the most effective and quickest therapy for MDD?

Answer 33

ELECTROCONVULSIVE THERAPY Not very popular, but it is more effective than any alternative therapy that exists for unipolar depression or bipolar disorder! Acts on the same pathways --> INCREASE 5HT and NE release Much fewer side effects, FASTER

Question 34

KETAMINE

Answer 34

Offers RAPID RELIEF OF DEPRESSION SYMPTOMS Clinical trials looking into it as an emergency treatment or for depression that doesn't respond to other medications

Question 35

General Recommendations for Anti-Depressants?

Answer 35

In general, need to be started ONE AT A TIME (lots of interactions) and wait for UP TO A MONTH TO SEE IF THEY ARE EFFECTIVE OR NOT! After that, it is appropriate to change classes or to use another drug in the same class (switching is common) Only if these show NO EFFECTS, should LITHIUM, MAOI or ECT be considered Generics are preferred (due to cost)

Question 36

What are the three types of Bipolar Disorders?

Answer 36

CYCLOTHYMIC -- Alternating between hypomania and mild-moderate depression; 1% lifetime risk; A significant number go onto develop FULL BLOWN BPD Bipolar II --> Alternations between MAJOR DEPRESSION and HYPOmania --> 0.5% life time risk; Significant number go onto develop... BIPOLAR II --> CLASSIC BIPOLAR - with FULL MANIC EPISODES after alternating with MAJOR DEPRESSION 0.5-1.5% lifetime risk

Question 37

LITHIUM

Answer 37

Mainstay as an effective PROPHYLACTIC against BOTH mania and depression This is a MOOD STABLIZER Usually takes about 7-10 days to work NOT USUALLY EFFECTIVE IN DEPRESSION PHASE or in UNIPOLAR DEPRESSION

Question 38

Lithium Mechanism of Action

Answer 38

Two mechanisms: Inhibits adenylyl cyclase --> lowering cAMP; this might contribute to some therapeutic effects via reducing NE or DA stimulated cyclic AMP Inhibits inositol phosphatase --> stopping regeneration of PIP2 in Phospholipase C G protein reactions This has a greater effect on the BRAIN because it relies on the regeneration cycle heavily --> NT receptors that are couple to this system include ALPHA 1 ADRENERGIC, 5HT, some muscarinic, some glutamate In the body, PIP2 is also made by the liver, so this drug won't completely reduce body levels

Question 39

Side Effects of Lithium

Answer 39

Has a very narrow therapeutic index! (0.6-1.5 mEq/L = therapeutic --> 2.5 mEq/L = TOXIC) LIKELY TERATOGEN during 1st Trimester (possible tricuspid valve malformation) Excreted via the KIDNEY --> reabsorbed in PCT --> THIAZIDE DIURETICS increase excretion of sodium and potassium at the distal tubule, and therefore INCREASE LITHIUM REABSORPTION DUE TO LESS COMPETITION!!!! Also, Lithium inhibits the action of ADH --> resembling Diabetes Insipidus (kidneys can't conserve water!) NSAID use and INTENSE EXERCISE will INCREASE LITHIUM LEVELS Causes WEIGHT GAIN May also alter THYROID FUNCTION and DEPRESS THE SINUS NODE

Question 40

Lithium ALTERNATIVES

Answer 40

Acute MANIC episodes --> usually controlled by an ANTIPSYCHOTIC (aripiprazole, risperidone, haloperidol) or a BENZO Usually added CONCURRENTLY with Lithium so that it can STABILIZE MOOD!

Question 41

Anti-Epileptic Drugs?

Answer 41

VALPROIC ACID, CARBAMAZEPINE, LAMOTRIGINE These antiepileptic drugs can be effective as mood stabilizers also, although they may not be as effective as Li and they cost more. Valproic acid or carbamazepine can be combined with Li in refractory patients. These drugs are worrisome for a few reasons --> they INTERACT WITH MANY DRUGS THROUGH p450 interactions, specifically oral contraceptives to below effective ranges (increase estradiol!) Associated with NEURAL TUBE DEFECTS