Antidepressants other drugs used in affective disorders

1
Antidepressants ? other drugs used in affective
disorders

• Martin Sterba, MSc.
• Department of Pharmacology

2
Definitions

• Affective disorders - mental illnesses
  characterized by pathological changes in mood
  (not thought compare with schizophrenia)
• Unipolar disorders
• Depression pathologically depressed mood (life
  time prevalence up to 17)
• Mania excessive elation and accelerated
  psychomotoric activity (rare)
• Bipolar disorder (manic-depressive illness)
  cycling mood
• severe highs (mania, event. hypomania) and lows
  (major depressive episodes)
• prevalence 1-5, life-time illness, stronger
  genetic background

3
Depression

• common mental disorder that presents with
  depressed mood, loss of interest or pleasure,
  feelings of guilt or low self-worth, disturbed
  sleep or appetite, low energy, and poor
  concentration (WHO def.)
• Major Depressive Episode Criteria/Core symptoms
• Five (or more) of the following symptoms have
  been present during the same 2-week period and
  represent a change from previous functioning at
  least one of the symptoms is either (1) depressed
  mood or (2) loss of interest or pleasure.
• depressed mood most of the day
• markedly diminished interest or pleasure
• significant weight loss /gain
• insomnia or hypersomnia
• psychomotor agitation or retardation, fatigue or
  loss of energy
• feelings of worthlessness or excessive or
  inappropriate guilt
• diminished ability to think or concentrate, or
  indecisiveness
• recurrent thoughts of death or suicidal ideation
  without a specific plan or a suicide attempt (!)

4
What is not depression

• it is not the same as a passing blue mood.
• It is not a sign of personal weakness or a
  condition that can be wished away.
• people with a depressive disease can not merely
  "pull themselves together" and get better.
• - no effect of encouraging to do so!
• without treatment, symptoms can last for weeks,
  months, or years.
• appropriate treatment, however, can help most
  people with depression.

5
Neurobiological theory of depression

• Monoamine (catecholamine) theory (1965) the
  underlying biological or neuroanatomical basis
  for depression is a deficiency of central
  noradrenergic and/or serotonergic transmission in
  the CNS
• Supported by
• pharmacological effect of antidepressants (TCA,
  MAOI)
• In the past, medication of hypertension with
  reserpine induced depression
• Contradiction
• several drugs (e.g. cocaine) increase the amount
  of these neurotransmitters in the CNS but are
  unable to treat depression
• the effect of antidepressants on neurotransmitter
  levels is relatively quick but onset of
  antidepressant action is significantly delayed
• Receptor theory the problem is in
  up-regulation of post-synaptic receptors and
  alterations in their sensitivity
• The antidepressant treatment increases the
  amount of monoamines in CNS and thereby gradually
  normalize the density/sensitivity of their
  receptors
• The precise pathophysiology of depression remains
  unsolved

6
Therapy of depression

• Pharmacotherapy
• Tricyclic antidepressants (TCA)
• Monoamine oxidase inhibitors (MAOI)
• Selective Serotonin Re-uptake Inhibitors (SSRI)
• Other and atypical antidepressant
• Serotonin-2 Antagonists/Reuptake Inhibitors
  (SARI)
• Serotonin and Noradrenaline Reuptake Inhibitors
  (SNRI)
• Noradrenaline and Dopamine Reuptake Inhibitors
  (NDRI)
• Noradrenaline Reuptake Inhibitors (NaRI)
• Noradrenergic/Specific Serotonergic
  Antidepressants (NaSSA)
• Duration of treatment 6 months after recovery
  (1st epizode), may be even life-long treatment in
  recurrent depression
• Non-pharmacological treatment
• Psychotherapy
• Light therapy
• Electroconvulsive therapy (ECT)

7
Tricyclic Antidepressants (TCAs)

• Chemical structure with characteristic
• three-ring nucleus lipophilic nature
• Originally developed as antipsychotics
• (1949), but were found to have no effect in
• this indication.
• Principal mechanism of action
• blockade of re-uptake of monoamine
  neurotransmitters noradrenaline (NA) and
  serotonin (5-HT) by competition for binding site
  of the carrier protein. 5HT and NA
  neurotransmission is similarly affected but the
  effect on the dopamine system is much less
  important (compare with cocaine)
• in most TCA, other receptors (incl. those outside
  the CNS) are also affected blockade of
  H1-receptor, ?-receptors, M-receptors

imipramine
8
Most important TCAs

• imipramine (a representative)
• desimipramine
• demethylated form, the active metabolite of
  imipramine
• amitriptyline
• nortriptyline
• demethylated form, the active metabolite of
  amitriptyline)
• Clinical use and efficacy is relatively close
  within the group the more significant difference
  is in their adverse effects

9
Pharmacokinetics

• Administered orally rapid absorption, however
  extensive first pass effect ? low and
  inconsistent BAV
• Strong binding to plasma proteins (90-95 bound).
  They are also bound in tissues wide
  distribution (high lipophilicity) large
  distribution volumes (ineffectiveness of dialysis
  in acute intoxications).
• Biotransformation in the liver (CYP450,
  N-demethylation and tricyclic ring hydroxylation)
  most of these metabolites are active! CYP450
  polymorphisms ! Glucuronidation ? inactive
  metabolites excreted in the urine.
• Elimination half-lives - generally LONG (T1/2
  10-80h). Elderly patients even longer T1/2,
  risk of accumulation.

10
Adverse effects

• TCA are effective antidepressants but their use
  is complicated by numerous troublesome adverse
  effects
• Anticholinergic (atropine-like) due to M-blockade
• Dry mouth, blurred vision, constipation, urinary
  retention (more in amitriptyline, less in
  imipramine) Palpitations, tachycardia
• Postural (orthostatic) hypotension reflex
  tachycardia - ?-blockade of adrenergic
  transmission in the vasomotor center (frequent in
  elderly)
• Sedation, drowsiness, difficulty in concentration
  (amitriptyline, H1-blockade)
• Sexual dysfunction (loss of libido, impaired
  erection)

? Possible problems with compliance ?!!!
11
Acute intoxication

• Very dangerous and relatively frequent
  patients with depression often have suicidal
  tendencies
• Precautions
• taking care about patient education (remind
  him/her that 2-4 week delay in the effect is
  anticipated and that it is NOT a failure of
  medication)
• therapy of concomitant anxiety/agitation
• prescription of limited quantities of TCA
• high risk patient should be treated under
  supervision of specialists or treated as
  inpatients

12
Acute intoxication

• Unfortunately a low therapeutic index
• Target systems the CNS and heart
• Initially excitement, hallucinations and delirium
  is observed, may be accompanied with convulsions.
  Coma and respiratory depression may follow.
  Pronounced atropine-like effects.
• Cardiac dysrrhythmias are very common
  tachycardia (antimuscarine action), atrial or
  ventricular extrasystoles, QRS complex widening,
  QT interval elongation. Ventricular fibrillation
  and sudden death may occur.
• Hypotension
• Treatment- diazepam (seizures), physostgmine???
• No effect of haemodialysis and hemoperfusion is
  practically ineffective

13
MonoAmine Oxidase Inhibitors (MAOI)

• The first compounds (iproniazid derivatives) were
  originally developed as antimycobacterial drugs
  by chemical modification of isoniazid molecule
  (1950s).
• Principal mechanism of action
• Inhibition of intracellular enzyme MAO in CNS
  neurons ( decrease in degradation
  of catecholamines and serotonin).
• antidepressant action is attributed to MAO-A
  enzyme isoform inhibition ? increased cytoplasmic
  pool of monoamines leading among other(s) to
  spontaneous leakage of monoamines.
• In contrast to other antidepressants, when given
  to normal non-depressed subjects they increase a
  motor activity and cause euphoria excitements
  (while TCA would cause only sedation and/or
  confusion). ?
  risk of abuse!

14
MAOI drugs

• Irreversible non-selective inhibitors
  (hydrazides)
• long lasting inhibition (up to 1-2 weeks)
  despite of the elimination rate of a drug
• phenelzine
• tranylcypromine
• Reversible Inhibitors of MAO-A (RIMA)
• moclobemide
• Great difference in adverse reactions between
  these groups
• Note Reversible inhibitors of MAO-B (e.g.
  selegiline) are used in the
• treatment of Parkinson's disease.

15
Adverse reactions and toxicity

• Hypertension
• Postural hypotension (in up to 1/3 patients)
• CNS stimulation tremor, excitement, insomnia,
  convulsions in overdose.
• Weight gain (increased appetite)
• Atropine-like adverse effects like in TCA but
  less common
• Rare severe hepatotoxicity (hydrazine MAOI)

16
Interaction with foods

• The most serious problem of this class of drugs
• Much less important in novel RIMA drugs like
  moclobemide
• Tyramine cheese and wine reaction
• some kind of foods contain high amounts of
  tyramine (natural indirect sympathomimetic
  produced during fermentation), which is however
  normally metabolized by MAO in the gut and liver.
  
• In depressed patients treated with MAOI, these
  enzymes are also inhibited ? bioavailability of
  tyramine is significantly higher which together
  with pharmacodynamic synergism ? strikingly
  increased noradrenaline transmission results in
  hypertensive crisis, severe headache and
  potentially fatal intracranial hemorrhage or
  other organ damage.
• Dietary precautions restriction in the
  consumption of some maturing cheeses, wine, beer,
  yogurts, bananas etc.
• This risk is minimal with modern RIMA drugs.

17
Interaction with drugs

• Hypertension hypertensive crisis
• TCA wash-out period (2 weeks) when switching
  these antidepressants! Lower risk in RIMA.
• levodopa (catecholamine precursor),
  sympathomimetics
• Serotonin syndrome (SSRI, TCA, opioids e.g.
  Pethidin)
• confusion, agitation and excitation, tremor,
  fever, sweating, nausea, diarrhea, sleep
  disruption
• prolongs and profounds the effect of
  benzodiazepines, antihistamines, alcohol
  (inhibition of liver enzymes low specificity)

18
Selective Serotonin Re-uptake Inhibitos (SSRI)

• More modern (1st drug fluoxetine available in
  1988) and safe antidepressants
• Principal mechanism of action
• selective inhibition of 5-HT (serotonin) reuptake
  ? gradual complex changes in the density and/or
  sensitivity both autoreceptors (5-HT1A) and
  postsynaptic receptors (important subtype 5-HT2A
  )
• Other indications of SSRI - anxiety disorders
  generalized anxiety, panic disorder, social
  anxiety disorder, obsessive-compulsive disorder
• 
  bulimia nervosa, gambling

19
Most important SSRI

• Fluoxetine
• Fluvoxamine
• Paroxetine
• Sertraline
• Citalopram

Enantioselective forms e.g. escitalopram
(S-enantiomer)
20
Pharmacokinetics

• Good absorption after oral administration
• Important biotransformation in the liver
• CYP450 - 2D6 and 2C19 isoforms (polymorphism ?
  interindividual variability in the clinical
  effect) and active metabolites (e.g. fluoxetine)
• Long half-lives of elimination(s)
• fluoxetine (T1/250h) active metabolite (T1/2
  240h)
• Drug interaction based on plasma protein binding
  and CYP blockade
• increased effect of co-administered TCA but also
  ?-blockers, benzodiazepines etc.

21
Adverse effects

• Relative improvement to other antidepressants
  (mostly mild)
• GIT nausea, vomiting, diarrhea
• Headache
• Sexual dysfunctions
• Restlessness (akathisia)
• Insomnia and fatigue
• Few patients experience an increase in anxiety or
  agitation during early treatment
• Serotonin syndrome upon intoxication or drug
  interactions

22
Other and atypical antidepressants

• Serotonin-2 Antagonists/Reuptake Inhibitors
  (SARI)
• trazodone (sedative effects)
• nefazodone (newer and improved) decreased some
  SSRI adverse reactions
• Serotonin and Noradrenaline Reuptake Inhibitors
  (SNRI)
• venlafaxine - pharmacodynamic like in TCA however
  improved profile of adverse reactions
• Noradrenaline and Dopamine Reuptake Inhibitors
  (NDRI)
• bupropion rather CNS activating effects (low
  sedation), usage severe depression smoking
  cessation treatment. Adverse reactions insomnia,
  excitation, restlessness, lowers epilepsy
  threshold
• Noradrenaline Reuptake Inhibitors (NaRI)
• reboxetine also rather activating
• maprotiline
• Noradrenergic/Specific Serotonergic
  Antidepressants (NaSSA)
• mirtazapine increased NA and 5-HT
  neurotransmission through blockade of their
  autoreceptors (low 5-HT adverse effects blocks
  also postsynaptic 5-HT receptors)
• Miscellaneous
• St Johns wort (Hypericum perforatum) a herb
  containing number of active compounds (among
  other hyperforin a MAOI). It was proved to be
  clinically effective and well tolerated, but it
  induces CYP450 (risk of drug interactions! E.g.
  it decreases the effect of ciclosporin which may
  result even in transplant rejection in
  transplanted patients)

23
Therapy of bipolar disorder

• Main aim to eliminate mood episodes, maximize
  adherence to therapy, improve functioning of the
  patients and eliminate adverse effects
• MOOD STABILIZERS
• Lithium
• Valproate
• Carbamazepine
• Lamotrigine
• Adjunctive agents (antidepressants and
  benzodiazepines)

24
Lithium

• Since 1949 - indication as a prophylactic
  treatment in bipolar disorder. Effective also in
  60-80 patients with mania or hypomania.
• Principle mechanism of action
• remains elusive though profound effects on second
  messenger systems (mainly IP3) is supposed.
• Pharmacokinetics
• administered orally (readily and almost
  completely absorbed)
• distribution - extracellular, then gradually
  accumulates in various tissues
• elimination 95 in urine (T1/2 20-24h when
  the treatment is abruptly stopped - slow 2nd
  phase of excretion /1-2 weeks/ representing Li
  taken up by cells occurs)
• only 20 of Li filtered by GF is excreted (80
  reabsorbed)

25
Lithium toxicity and adverse reactions

• Acute intoxication, symptoms
• GIT vomiting, profuse diarrhea
• CNS confusion, tremor, ataxia, convulsions,
  coma.
• Heart arrhythmias, hypotension
• Unfortunately there is no specific antidote ?
  supportive treatment
• Toxicity of long-term therapy
• Renal toxicity the kidney's ability to
  concentrate the urine is decreased
• Adverse reactions polyuria and polydipsia,
  weight gain, GIT disturbances (vomiting, nausea,
  dyspepsia), alopecia
• Drug interactions thiazides increased Li
  reabsorption ? intoxication Critical importance
  of TDM to reach desirable effects without risk of
  toxicity!
• The effects as well as toxicity correlates much
  more better with plasma concentrations than with
  dose. The range of plasma concentrations is
  narrow
• 0.5-1.0 mmol/L (above 1.5 mmol/L toxic effects
  appear)