PharmacologySection 10.

Antidepressants and mood stabilizing drugs

Marta Jóźwiak-Bębenista

martia1@tlen.pl

Affective disorders psychiatric diseases

1. Major depressive disorder (MDD)

monopolar depression/ unipolar affective disorder Dysthymic disorder Seasonal affective disorder (SAD) Postpartum depression („baby blues”) Premenstrual dysphoric disorder (PMDD) Substance-iduced mood disorder

2. Bipolar affective disorder (BAD)

manic depressive disorder alternating manic, normal and depressive episodes

Depression everyone feels "blue" at certain

times transitory feelings of sadness are

perfectly normal clinical depression is a serious

condition that affects a person's mind and body.

all aspects of everyday life including eating, sleeping, working, relationships, and how a person thinks about himself/herself.

cannot simply will themselves to feel better or „snap out of it”

symptoms can continue for weeks, months, or years at untreated patients

Statistics and Information about depression

Depression affects almost 10% of the population, or 19 million Americans, in a given year

During their lifetime, 10%-25% of women and 5%-12% of men will become clinically depressed

Women are affected by depression almost twice as often as men

- hormonal changes brought on by puberty, menstruation, menopause, and pregnancy.

- suicide is serious risk for men with depression, 4 times more likely than women

It can affect any person at any age (usually 25-44)

Statistics and Information about depression

Two-thirds of those who are depressed never seek treatment and suffer needlessly

- personal weakness or character flaw - do not recognize the signs or symptoms that

something may be wrong.

80%-90% of those who seek treatment for depression can feel better within just a few weeks

- one-third of those who are depressed

actually receive treatment Depression as the "common cold" of

mental illness.

The economic cost of depression is estimated to be over $30 billion each year

Symptoms of depression Emotional usually worst in the morning

– depressed mood most of the day, nearly every day – sad, anxiety or “empty” feelings

– lack of pleasure in usual activities

– no interest in the future.

– restlessness, irritability, pessimism– feelings of guilt, worthlessness, helplessness, and

hopelessness– difficulty thinking, such as concentrating or making

decisions, memory impairment

- recurrent thoughts of death or suicide

Symptoms of depression Physical (biological)

– change in sleep patterns. usually early morning awakening inability to sleep sleeping too much

– change in appetite and weight decreased appetite with weight loss (most common) sometimes increased appetite with weight gain

– loss of energy or fatigue

– unexplained physical problems: headaches, stomach problems, aches and pains,…

In order to make diagnosis of a major depressive disorder, the symptoms

(f ive or more) must have been present without a return to normality for at least

2 weeks.

People who are depressed may not experience all of these symptoms. Some will have many symptoms, others will have just a few.

Causes of depression

It is not fully known what exactly causes clinical depression.

Numerous theories: biological causes genetic causes environmental influences

Clinical depression is most often caused by the influence of more than just one or two factors.

Biological causes of depression

1.monoamine theory

↓ Concentration in the synaptic cleft

↓ Neurotransmission in the brain

Deficit of monoamines: NA, 5-HT, DA in the brain

The drugs, that will be increasing neurotransmission, in aminergic neuron systems will be used in

depression treatment.

2. Cortisol- hormone that the body produces in response to

stress Depressed patients havea raised baseline cortisol concentration

Biological causes of depression

inadequate neurotransmitter signalling– functional deficit of NA, DA and 5-HT

(monoamine theory)

– desensitization of β-adrenergic and 5-HT2A receptors

– dopaminergic system– GABA– peptidergic systems (AVP, opiates)

Reducing the central serotonin, noradrenaline, and dopamine

concentration can lead to depression

Drugs that increase the central serotonin, noradrenaline, and

dopamine concentration improve depression!

Causes of depression genetic causes- the result of what patients inherit from parents- If one or both

parents have a vulnerability to depression, then it can be transmitted to their children.

- if one identical twin suffers from depression or manic-depressive disorder, the other twin has a 70% chance

environmental influences- stress, breakup of important attachments (lack of

loving parents, death of a parent during childhood), physical illness (medication, substance abuse)

Treating depression

1.      Antidepressant drugs

2.      Electroconvulsive therapy (ECT) - success rate of 78%

- ECT for individuals whose depression is severe or life threatening or is effective in cases where antidepressant medications do not provide sufficient relief of symptoms

3.      Psychotherapy- learning about their disorder, learning to identify and avoid

situations that may induce another depressive episode, view themselves and their situations more realistically, and to improve their interpersonal relationship skills.

Herbal remedies Derived from

Hypericum perforatum Most popular remedy in

the world Appears effective for

milder depression Side effects: phototoxicity available without

prescription 900-1800mg/day is

recommended doseSt. Johns Wort

Antidepressants

Antidepressants

Tricyclicantidepressants

TCAs

Selective serotoninreuptake inhibitors

SSRIs

Monoamine oxidase

inhibitorsMAOIs

Mood stabilizer/

other drugs

Antidepressants

Antidepressants

Tricyclic antidepressants

TCAs

Selective serotoninreuptake inhibitors SSRIs

Monoamine oxidase

inhibitorsMAOIs

Mood stabilizer/

other drugs

Since the 1950s Imipramine (Tofranil) Three-ring chemical structures Less popular choice than the new generation of

antidepressants Similar therapeutic efficacy Choice of drug (side effects/duration of action) Change of medicine after three weeks

Tricyclic antidepressants

Mode of action:beefing up the brain`s supply of NA, 5-HT levelsØ monoamine (NA, 5-HT) reuptake into presynaptic nerve from the synaptic cleft → ↑concentration of NE, 5-HT → ↑neurotransmissionThe antidepressant effect of TCAs occur after two weeks or longer of continued treatment !!!

- decreased reuptake immediate effect not the antidepressant effect

- long- term adaptational changes

in receptors→→ the antidepressant effect !!!

- reuptake blocking potency doesn’t correspond with clinical potency

Ø receptors for ACh, HA, 5-HT, α

The important drugs of TCAs Tricyclic

Antidepressants (TCAs)

• amitriptyline (Elavil, Endep)

• clomipramine (Anafranil)

• desipramine (Norpramin, Pertofrane)

• doxepin (Adapin, Sinequan)

• imipramine (Imavate, Janimine, Presamine, Tofranil)

• nortriptyline (Aventyl, Pamelor)

• protriptyline (Vivactil)

• trimipramine (Surmontil)

Heterocyclic Antidepressants

Second-generation • amoxapine (Ascendin) • maprotiline (Ludiomil)

Pharmacokinetics

1. Absorption and distribution good absorption from GI tract upon oral

administration lipophilic properties good BBB penetration long half-life (for imipramine 4-18 h) first-pass effect inconsistent and low

bioavailability– patient’s response dose adjustment

Pharmacokinetics

2. Fate TCAs are metabolized by enzymes

Cyt.P450 metabolites pharmacologically active! Amitriptyline → nortriptyline* Imipramine → desipramine* Active metabolites prolong

pharmacological effects excretion urine

Therapeutic uses of TCAs

 severe depression - also prevents recurrence

 depression with anxiety  panic and phobic disorders  bet-wetting in children (imipramine)

 chronic or psychogenic pain bipolar disorder

Side effects of TCAs 1. antimuscarinic effects: dry mouth, blurred vision,

urinary retention, constipation and aggravation of glaucoma and epilepsy

2. postural (orthostatic) hypotension reflex tachycardia

3. cardiovascular (heart failure, hypertension, hypotension, sudden death, arrhythmias, ECG changes)

4. sedation

5. hormonal effects (loss of libido, impotence)

6. others: gastric irritation, weight change, allergic skin reactions and jaudince

Contraindications to TCAs

       prostate        narrow angle glaucoma        recent myocardial infarction        heart block, heart failure arrhythmias        epilepsy

Drug interaction of TCAs  MAOI → „serotonin syndrome” - life threatening! tachycardia, hypertension, hyperactivity, hyperpyretic crisis, convulsions, coma TCAs should not be given in conjunction with- or within at least two weeks of treatment with -a MAOI.

TCA+MAOI= monitoring! Drugs having anticholinergic actions Central nervous system depressant (alcohol, barbiturates) Hepatic enzyme inhibitors (cimetidine, SSRI) Hepatic enzyme inducers (carbamazepine) Oral coumarin anticoagulants (↑increase effect) Guanetydyna (↓decrease effect)

Tolerance and withdrawal with TCA’s

Tolerance generally develops to anticholinergic and sedative side effects within a short time

An occasional withdrawal syndrome is reported with abrupt discontinuation from high dosages.

True dependence, however, does not occur

TCAs can be used for prolonged treatment without loss of effectiveness

Tricyclic antidepressants

(!) unmask manic behavior in BAD (!) low TI suicidal attempts acute

toxicity (arrhytmias, respiratory depression, convulsions,…)

monitored closely

Antidepressants

Antidepressants

Tricyclicantidepressants

TCAs

Selective serotoninreuptake inhibitors

SSRIs

Monoamine oxidase

inhibitorsMAOIs

Mood stabilizer/

other drugs

Selective serotonin-reuptake inhibitors SSRIs

Introduced in the 1980s as a new antidepressants

Replaced the TCAs Affect the serotonin-containing nerves safe, better tolerability, less severe side

effects Less toxic in overdose than TCAs Do not require blood monitoring

Mode of action of SSRIs Specifically inhibit 5-HT

reuptake from synaptic cleft into presynaptic nerve terminals

↑concentration of 5-HT in the synaptic cleft→ long term adaptational changes ↑serotonin neurotransmission

no effect on NE reuptake don`t have affinity for M, HA,

5-HT and α receptors

SSRIs include:  - Citalopram (brand name: Celexa),  - Fluoxetine (brand name: Prozac),  - Paroxetine (brand name: Paxil)  - Sertraline (brand name: Zoloft)  - Fluvoxamine

Fluoxetine is now the most widely prescribed antidepressant in the United States!

Pharmacokinetics of SSRIs1. Absorption and distribution oral administration rapidly absorbed and distributed Active metabolites! – citalopram, fluoexetine, sertraline fluoexetine → norfluoxetine* Norfluoxetine is 3x more selective, potent than

parent drug fluvoxamine(+) no active metabolite t0.5 ~ 15 h

fluoexetine t0.5 up to 30 days

The long half-life of fluoxetine and its metabolite imposes cautious management when treatment

is to be changed, because the drug lingers in the blood for some time after the treatment has been

discontinued,

this way increasing the risk of drug interactions.

Side effects of SSRIs

     

•   gastrointenstinal disturbances: nausea, vomiting, diarrhoea

•    headache, insomnia,

•    anxiety, agitation

•    sexual dysfunction (loss of libido, impotence)

•    allergic skin reactions

•    weight loss

•    tremors, seizures

•    serotonin syndrome!

   SSRIs have fewer side effects than TCAs (fewer anticholinergic effects  and lower cardiotoxicity)

Therapeutic uses of SSRIs: Efficacy similar to that

of TCAs Major depression

Clinical advantages:

- no anticholinergic effects

- no orthostatic hypotension

- no weight gain

- no toxic in overdose

- lower cardiotoxicity

↑ acceptability

Therapeutic uses of SSRIs:

1. depression in early stages

2. minor depressive illness

3. anxiety disorders:

        - panic attacks

        - obsessive-compulsive disorder

2. eating disorders (bulimia nervosa, anorexia nervosa)

3. chronic pain (e.g. pain associated with diabetic neuropathy)

4. menstrual syndrome

Drug interactions of SSRIs

-    MAOI → „serotonin syndrome” It should wait at least two weeks between stopping MAOIs and starting an SSRI, or at least five weeks after stopping an SSRI and starting an MAOI.- TCAs monitoring!

-    tryptophan (headache, nausea, sweating and dizziness)

-    warfarin (excess bleeding)

Drug interactions of SSRIs

SSRIs are inhibitors of hepatic cytochrome P450 isoenzyme!

metabolizes: - ↑ neuroleptics,

- ↑ TCAs,

- ↑ some antiarrhythmics

- ↑ beta blockers paroxetine> fluoxetine> sertraline> citalopram>fluvoxamine

- Hepatic enzyme inhibitors (cimetidine, SSRI)

-    Hepatic enzyme inducers (carbamazepine)

Antidepressants

Antidepressants

Tricyclicantidepressants

TCAs

Selective serotoninreuptake Inhibitors

SSRIs

Monoamine oxidase

inhibitorsMAOIs

Mood stabilizers/Other drugs

MAOIs Adverse reactions associated with MAOIs

are generally more frequent and severe than with other antidepressants.

- reducing the dosage

- monitoring the patients Use of MAO inhibitors is now limited,

because of the complicated dietary restrictions required of patients taking MAOIs!

Mechanism of action of MAOIsInhibit the action of monoamine oxidase- MAO

MAO-A

MAO-B

Tyramine

5-HT, NA

Dopamine,

phenylethylamine

1. irreversibly or reversible inactivation MAO

2. nonselective or selective - MAOI-A and MAOI-B

selective + reversible: moclobemide less ADEs, INTs

Mechanism of action of MAOIs

Inactivation of monoamine oxidase concentration of

NA, 5-HT, DA in thepresynaptic neuron

leakage ofmonoamines intosynaptic space

monoaminetransmission

MAOIs:

1. Non-reversible/non-selective monoamine oxidase inhibitors (MAOIs)

phenelzine - the hydrazine derivative, amphetamine-like activity. isocarboxazid - the hydrazine derivative tranylcypromine - non-hydrazine derivatives, amphetamine-like

activity.

2. Non-reversible/ selective monoamine oxidase inhibitors Selegilina MAO-B

3. Reversible/ selective monoamine oxidase inhibitors Moclobemid

Actions and Pharmacokinetics of MAOIs

Actions: antidepressant action after 2-4 weeks amphetamine-like stimulatory

Pharmacokinetics: oral administration long duration after discontinuation of

treatment (~ 2 weeks) → irreversibly inactivated

Washout period The irreversibility of the binding of the

enzyme by IMAO is a serious problem Effects of MAOIs continue until enough

new, unbound MAO is synthesized ! Enzyme regeneration occurs several

weeks after the ending of treatment wash-out period of at least 2 weeks

should be allowed between stopping a MAOI and starting a TCA or a SSRI

During this 2 weeks the patients should continue dietary and other restrictions until this time has elapsed.

Therapeutic uses of MAOIs

atypical depression (e.g appetite disorders) depression

– if unresponsive to TCAs– if associated with strong anxiety– if associated low psychomotor activity

resistant depression facial pain phobic states

Adverse effects/interactions of MAOIs

tyramine rich food (cheese, red wine, beer, chicken liver) „cheese reaction” – tyramine not inactivated by MAO catecholamine

release tachycardia, headache, nausea, hypertension, cardiac arrhytmias, stroke

– develops within 30 minutes to 1 hour after ingestion of the food

– antidote phentolamine, prazosin

Sympathomimetic agents (dopamine, ephedrine), opioid analgesics, narcotics

TCAs or SSRIs „serotonin syndrome”– washout period of ~ 2 weeks when therapy change

MAO blockade has the potential of serious and indeed lifethreatening consequences if the subject is exposed

to certain agents, which would normally be metabolized by this same

enzyme.

The patients treatment MAOI must therefore be educated to avoid tyramine containing foods and

some drugs.

For these reasons, the MAOIs are no longer considered as first-choice antidepressants and are usually only prescribed after other options

have failed.

Foodstuffs (high in tyramine) to avoid with MAOIs

Drugs to avoid with MAOIs:1. sympathomimetic agents, such as:

         -dopamine

         -ephedrine

         -levodopa

         -pseudoephedrine

2. opioid analgesics

3. amphetamine

4. dextromethorphan

5. CNS depressant (e.g alcohol, narcotics)

6. SSRIs, TCAs

Other side-effects

a. Sleep disturbances, drowsiness

b. Orthostatic hypotension

c. Weight gain

d. Sexual dysfunction

e. Insomnia

f. Peripheral neuropathy (pyridoxine deficiency)

Contraindications to MAOIs:          pheochromocytoma          congestive heart failure          liver disease

Antidepressants

Antidepressants

TricyclicADs

Selective serotoninreuptake inhibitors

Monoamine oxidase

inhibitors

Other drugs

Other drugs

Second-generation • bupropion (Wellbutrin)• trazodone (Desyrel)• amoxapine (Ascendin) • maprotiline (Ludiomil)

Third-generation• mirtazapine (Remeron)• venlafaxine (Effexor,

Efectin)• nefazodone (Serzone)

Heterocyclic Antidepressants

The new generation drugs

Second generation antidepressantsSecond generation antidepressantsTrazodoneTrazodone- SSRI, Ø NA and 5-HT receptors - may be used in schizophrenic patientsMaprotilineMaprotiline- selective noradrenaline reuptake inhibitor (NARI)BBupropionupropion (Wellbutrin)

- selective dopamine reuptake inhibior, antinicotine treatment

Third-generation antidepressantsThird-generation antidepressantsVenlafaxineVenlafaxine

– Serotonin-noepinephrine reuptake inhibitors (SNRIs) – clinical profile like SSRIs, quick onset of action

Mirtazapine Mirtazapine - noradrenergic and specific serotonergic

antidepressant (NaSSA)

- Ø presynaptic NA and 5-HT receptorsNefazodonNefazodon ~ trazodon, less sedating

Other atypical Other atypical antidepressants:antidepressants:

MianserineMianserine–presynaptic α2 blocker–A: sedative, anxiolytic

TianeptineTianeptine 5-HT reuptake (???)–(+) few ADEs–ADE: hepatitis (rare)

ViloxazineViloxazine NE reuptake–(+) not cardiotoxic or cholinolytic

Drug choice The right drug and the right dose for the individual

patient must be accomplished empirically and depends on:

- the clinical characteristics of the patient`s illness- the drug`s adverse effect profile- toxicity in overdosage and dosing schedules- the past history of the patient`s drug experience The greater tolerability of the SSRIs and SNRIs,

NaSSAs make them the preferred agents for most patients

If there are no medical contraindications or no risk of suicide, a TCA can be used

Drug choice MAOI – atypical depression

One third of patients do not respond to any single treatment

unresponsive patients

SSRI+TCA (desipramine) / Bupropion / Mirtazapine

lithium+SSRI

A generally accepted strategy is to begin treatment with an SSRI in mild to moderate outpatient depression

and then augment by adding a drug of a different class for more impaired

patients

Bipolar disorders

also known as manic depression or manic-depressive illness

Bipolar disorders Moods shift between two extremes For a period of time the person

experiences the symptoms of depression (the depressive phase), then his mood will shift into a period of mania (euphoria)

between these extremes a period of normal functioning

the manic phase can be enjoyable distressing, disruptive to people`s life

ManicMania is caused by an overproduction of neurotransmitters in the brain.

- lots of energy - extremely active and talkative - extremely happy or sometimes extremly angry - restless and irritable - racing thoughts - delusions - unable to sleep much - voices or see things that aren`t there – hallucinations - unrealistic beliefs in one's abilities and powers - abuse of drugs, particularly cocaine, alcohol, sleeping medications - a lasting period of behavior that is different from usual

A manic episode is diagnosed if elevated mood occurs with three or moreof the symptoms most of the day, nearly every day, for 1week or longer.

Bipolar disorder as a spectrum or continuous range

A mild to moderate level of mania is called hypomania. The patient shows signs of mania but doesn`t have delusions or hallucinations. In a hypomanic state, the patient may be able to continue with his life as normal.

A depressive episode is diagnosed, if five or more of the symptoms of depression occur most of the day, nearly every day, for a period of 2 weeks or longer. So the depressive episodes in BPAD are clinically identical to depression in the absence of previous manic episodes.

Bipolar disorder 2-3 million people suffer from

bipolar depression (1-2% of the population)

genetic factor (15% of children with one bipolar parent)

begins during adolescence or early adulthood

alcohol and drug abuse or anxiety disorders

better controlled if treatment is continous than if is on and off!

What It's Like Living With Bipolar Disorder?

Joseph is feeling on top of the world. He has just come off a period where it was so difficult for him to do anything that he wanted to do. In fact, for a few months, he didn’t do anything. He just stayed in the house, most of

the time sleeping.

It is certainly different now. In fact, Joseph is almost always out of the house. He only needs two to three hours sleep a night and he feels that

he has the energy of a bull.

Joseph is spending most of his time on a new project. He is working on a new business venture that he knows is going to make him a fortune.

Somewhere in the back of his mind he remembers that he has tried to start new businesses on numerous occasions and they have always

resulted in financial disaster. However, those failures are in the back of Joseph’s mind now because he knows that this idea is a sure winner.

He is spending most of his days trying to convince banks to lend him the money. He cannot understand why the banks that he has visited so far seem so negative, but Joseph is sure that he will find a bank soon that

will advance him the large sum of money that he needs.

He has spared no expense in this effort. Joseph has gone to the best stores and purchased a new wardrobe. He has ordered the latest in

computer equipment. He also has hired a commercial realtor to find him modern offices.

Joseph has not told his family about his new idea because they always rain on his parade. They are negative about all of his ideas. But he

knows that they do not have the vision that he has and that they will eat their words when they see the millions that he is going to make with his

new venture.

Treatment of bipolar disordersmedication – mood stabilizerssupportive psychotherapy occasionally ECT

Mood stabilizers are the usual treatment for bipolar illness. They prevent extreme mood

swings. These drugs must be taken long term even when the patients feel well.

Mood stabilizers 1. Lithium- this is the most common treatment and it works

for about 60% of people. 2. Anticonvulsants drugs (such as Carbamazepine(Tegretol),

valproate (Depakote), gabapentin (Neurontin) and lamotrigine Lamictal), these are given when lithium doesn`t work or when lithium is unsuitable

Other:3. antidepressants (such as bupropion (Wellbutrin)or

sertraline (Zoloft)),4. neuroleptics (e.g. haloperidol) 5. benzodiazepines (e.g. lorazepam)

BPAD is treated with a combination of mood stabilizers, antipsychotics and antidepressants

Lithium Mode of actions – unknown, proposed: mediated

via effects on the IP3 and DAG second-messenger systems

Efficacious: - acute mania - prophylaxis of classical bipolar disorder

- mania/hypomania-depression

the onset of action (7-10 days) excreted by the kidney the high frequency of non-adherence to lithium

treatment (30-50%)

Lithium narrow therapeutic range(0.8-1.1 mmols/l)

necessity of constant monitoring of plasma lithium levels heart, kidney, thyroid function

extremely toxic!

-1.5-2.0 mmol/liter → anorexia, vomiting, diarrhea, tremor, ataxia, confusion, sleepiness.

- 2.0 mmol/liter → impaired consciousness, convulsions

lethal in overdose hemodialysis

Adverse effects and toxicity of lithium

impairment, thirst, nausea acne, loose stools tremor goiter, hypothyroidism polyuria and polydipsia edema weight gain teratogenic

Drug interactions

Many medications interact adversely with Lithium

1. carbamazepine

2. antipsychotics (haloperidol)

3. cardioactive drugs ( digoxin, angiotensin-converting enzyme inhibitors)

4. diuretics: thiazides and ACE inhibitors

5. nonsteroidal anti-inflammatory drugs

Carbamazepine antiepileptic drug reasonable alternative to lithium used to treat acute mania, mixed state and

also for prophylactic therapy The mode of action is like of lithium

possible mediated via effects on second-messenger systems

Carbamazepine used alone or in combination with lithium.

Carbamazepine potent inductor of hepatic cytochrome P450

isoenzyme system Carbamazepine induces its own

metabolism! many drug interactions: 1. Lithium- increases the neurotoxicity of

carbamazepine. The combination of lithium and carbamazepine -more effective than either drug alone.

2. Antipsychotics - drowsiness and ataxia 3. TCAs - ↓concentration 4. MAOIs - cheese reaction

Adverse effects of carbamazepine

drowsiness, diplopia, nausea, rashes headache weight gain teratogenesis hematologic disturbances (agranulocytosis,

leucopenia) The plasma concentration of carbamazepine

must be monitored!

Valproic acid (valprote) an antiepileptic with antimanic effects some patients who have failed to respond to

lithium Adverse effects: - gastrointenstinal effects(nausea, vomiting,

diarrhea), - CNS effects (sedation,tremor) - hematological effects (thromobocytopenia,

leucopenia) - Hair loss Mode of actions: enhance the syntesis and

release of GABA

Divalproex sodium mixture of valproate sodium and valproic

acid bioavailability and tolerability low drug-drug interaction no proven long term risk fewer gastrointestinal side effects

Lamotrigine an antiepileptic well tolerated in bipolar affective disorder role in treating the depressive phase of

the illness