Antidepressants

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Antidepressants

• Depression is a disorder of mood. The symptoms of
  depression are intense feelings of sadness,
  hopelessness, despair, loss of energy, alteration
  of sleep and eating patterns and anhedonia.
  Suicidal ideation is common even what may appear
  to be mild clinical depression.

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Prevalence of Depression
Australia 2004-2005
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Mechanism of Antidepressant Drugs

• Most clinically useful antidepressants potentiate
  (directly or indirectly) the central actions of
  NE and/or serotonin (5-HT).
• Given the time course of the clinical response to
  antidepressants it may be the down-regulation of
  presynaptic inhibitory receptors allowing for
  prolonged action of neruotransmitters in the
  synaptic cleft and enhanced transmission of the
  post synaptic neurons that leads to improvement
  of mood.

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SSRI Mechanism
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Selective Serotonin Re-uptake Inhibitors

• Selective serotonin reuptake inhibitors (SSRIs)
  specifically inhibit 5-HT reuptake at the
  presynaptic terminal (there is also some NE
  reuptake inhibition but these drugs are very
  selective for 5-HT, dopamine reuptake is not
  effected).
• Tricyclic-antidepressants nonselectively inhibit
  reuptake of both NE 5-HT. This selectivity
  prevents side effects commonly experienced with
  TCAs (orthostatic hypotension, sedation,
  xerostomia and blurred vision).
• This lack of side effects results in a TI much
  greater than other antidepressant drugs, SSRIs
  have largely replaced TCAs (the first
  effective/specific antidepressant drugs) and
  MAOIs.

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Selective Serotonin Re-uptake Inhibitors
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serotonin
prozac
paxil
celexa
zoloft
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• Actions SSRIs block the reuptake of 5-HT leading
  in increased concentrations in the synaptic cleft
  resulting in greater post-synaptic neuronal
  activity.
• Mood elevating effects require 2 weeks and
  maximum effect may require 12 weeks or more.
• 40 of patients will fail to respond to adequate
  doses of an SSRI , but may respond to another
  SSRI.
• Overall 80 will respond to an SSRI. Of note
  these drugs have no effect on the mood of normal
  individuals.
• Therapeutic uses The primary indication for
  SSRIs is endogenous depression. Other
  psychiatric disorders may also respond to these
  agents, OCD, panic disorder, generalized anxiety,
  premenstrual dysphoric disorder and bulimia
  nervosa.

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• Pharmacokinetics
• These are well absorbed after oral
  administration. The volume of distribution far
  exceeds body mass (15-30L/kg). T1/2 range between
  16-36 hours, allowing single daily doses. They
  undergo extensive P450 metabolism and conjugation
  (glucuronide or sulfate). Metabolites are not
  active. Excretion is primarily through the
  Kidneys except paroxetine and sertraline which
  also undergo fecal excretion.

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• Prozac deserves individual consideration, its
  t1/2 is 50 hours and it is produced in a
  controlled release formulation allowing once per
  week dosing. Prozac metabolism generates an
  active metabolite of equal potency as the primary
  compound.

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• Adverse affects
• Sleep disturbances Paroxetine fluvoxamine are
  sedating, fluoxetine has some stimulatory effect.
• Sexual dysfunction Sexual dysfunction is a
  common side effect but often under self reported,
  it requires inquiry to discover.
• Use of these agents in children adolescents is
  associated with a 2 incidence of increased
  suicidal ideation.
• Overdoses All SSRIs have the potential cause a
  serotonin syndrome characterized by hyperthermia,
  muscular rigidity, myoclonus and altered mental
  status, particularly when used in combination
  with MAOIs.

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Serotonin/Norepinephrine Re-uptake Inhibitors

• These agents block the re-uptake of both 5-HT
  NE. These may be effective in those unresponsive
  to SSRIs. SNRIs have been shown to be effective
  in treating neuropathic pain (chronic pain) that
  frequently accompanies depression (like TCAs)
• Venlafexine (Effexor) At low doses this agent
  blocks 5-HT reuptake, at higher doses NE reuptake
  is impaired. The t1/2 of the parent compound and
  active metabolites is 11 hours.
• Duloxetine (Cymbalta) This agent blocks reuptake
  of both 5-HT NE at all doses. It undergoes
  extensive hepatic metabolism and should be used
  cautiously in those with poor liver function.
  Urinary excretion precludes use in those with
  poor renal function. This agent is highly bound
  to plasma proteins.

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Tricyclic Antidepressants

• These were the first drugs to be consistently
  effective at relieving depression in large number
  s of depressed patients. They block NE 5-HT
  uptake into the neuron. All have similar
  therapeutic efficacy, the choice of agent depends
  on patient tolerance of each drugs side effects.
  These drugs are useful in patients not responding
  to SSRIs.

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• Mechanism of action
• TCAs are potent inhibitors of neuronal reuptake
  of NE 5-HT into presynaptic nerve terminals,
  they do not block DA reuptake.
• TCAs block serotonergic, a- adrenergic,
  histaminergic and muscarinic receptors. It is
  unclear that this plays a role in therapeutic
  effect but is the cause of a number of side
  effects of these agents.
• Actions TCAs elevate mood, improve mental
  alertness, increase activity and decrease morbid
  preoccupation in 50-70 of depressed individuals.
  Mood elevation requires two weeks or longer.
  Tolerance dose not develop to the therapeutic
  effects but does develop to some side effects.
  As with SSRIs these agents show no mood altering
  effects in those with normal mood.

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• Therapeutic uses TCAs are effective in the
  treatment of severe major depression. They have
  been shown to be effective in the treatment of
  chronic pain (neuropathic pain) (especially
  amitriptyline).
• Pharmacokinetics TCAs are well absorbed orally
  and widely distributed due to their lipophilic
  nature. They have prolonged T1/2 and variable
  first pass effects. Hepatic metabolism involves
  both the P450 system and glucuronidation with
  urinary excretion of the inactive metabolites.

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• Adverse effects
• Blockade of muscarinic receptors causes blurred
  vision, xerostomia, urinary retention,
  constipation and aggravation of glaucoma.
• Epilepsy can be exacerbated by these agents.
  Increased catchecholamine levels peripherally can
  result in cardiac stimulation particularly with
  overdose. a-receptor blockade caused orthostatic
  hypotension and tachycardia.
• Sedation eith these agents may be significant,
  consumption prior to retirement may use this side
  effect to advantage, insomnia is a frequent
  complaint in depression.
• TCAs should be used with caution in those with
  bipolar disorder as they may unmask and/or
  exacerbate manic behavior.
• These agents have a relatively narrow TI
  (imipramine (tofranil) can be lethal at only 5-6
  times the average daily dose). Fatalities in
  isolated TCA overdose are associated with
  irreparable cardiac arrthymias.

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Uptake Inhibitors
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Monoamine Oxidase Inhibitors

• Monoamine oxidase is a mitochondrial enzyme found
  in nerve and other tissues. In neurons MAO
  functions to inactivate excess monoamine
  neurotransmitters (NE, DA, 5-HT). MAO inhibitors
  may reversibly or irreversibly inactivate MAO
  allowing monoamines to accumulate in the
  presynaptic nerve terminals and leak into the
  synaptic cleft. MAOIs are in limited use due to
  the dietary restriction required with their use.

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• Mechanism of action Most MAOI form stable
  complexes with the enzyme causing irreversible
  inactivation resulting in increased stores of
  monoamines in neurons and diffusion of
  neurotransmitter into the synaptic cleft. This
  effect is not limited to the CNS, peripheral
  action interferes with metabolism of a number of
  drugs and chemicals, tyramine a normal component
  of many foods.
• As with other antidepressants the chemical effect
  is immediate but the mood elevating effect
  requires a few weeks.
• Therapeutic uses These agents are limited to
  those not responding to less potentially toxic
  agents. They may be useful in phobic disorders
  and atypical depression.
• Pharmacokinetics These drugs are well absorbed
  orally. Regeneration of MOA activity requires
  up to four weeks after cessation of drug use.

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• Adverse effects MAOIs are associated with
  potentially severe side effects often these are
  unpredictable.
• Excess tyramine is found in a number of foods
  (beer, red wine, chicken livers, aged cheese,
  etc.) normally this is metabolized by gut MOA.
• Tyramine causes the release of large amounts of
  catecholamines from peripheral nerves this can
  cause headache, tachycardia, hypertension
  (hypertensive crisis), arrhythmias and stroke.
  Fatalities can common with concomitant use of
  some drugs.

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Treatment of Mania Bipolar Disorder

• Lithium salts are used prophylactically for the
  treatment of manic-depressive patients and
  treatment of manic episodes. 60-80 of those
  treated respond favorably.
• The mechanism of action of lithium is unknown it
  is thought to interfere with the generation
  /recycling of an intracellular second messenger
  phosphatidylinositol bisphosphate (PIP).
• The therapeutic index for lithium is relatively
  low. It may interfere with thyroid function.
  Lithium produces no noticeable effect in normal
  individuals.

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• Electroconvulsive Therapy