05 antidepressants by ravikiran
TRANSCRIPT
PharmacologySection 10.
Antidepressants and mood stabilizing drugs
Marta Jóźwiak-Bębenista
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