1. Antidepressants  other drugs used in affective disorders
Martin Sterba, PharmD.,PhD.
Associate professor
Department of Pharmacology
2013

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 Major Depressive Episode Criteria/Core symptoms
Five (or more) of the following symptoms have been present during the same 2-week period;
depressed mood most of the day…
markedly diminished interest or pleasure (anhedonia)
feelings of worthlessness or excessive or inappropriate guilt
recurrent thoughts of death or suicidal ideation without a specific plan or a suicide attempt (!)
significant weight loss /gain
insomnia or hypersomnia
psychomotor agitation or retardation
fatigue or loss of energy
diminished ability to think or concentrate, or indecisiveness

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 effects of antidepressants (TCA, MAOI)
In the past, medication of hypertension with reserpine induced depression
Contradiction:
antidepressants induce rapid change in neurotransmitters, 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 Non-pharmacological treatment
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
Principal mechanism of action:
blockade of re-uptake of monoamine neurotransmitters noradrenaline (NA) and serotonin (5-HT)
Effect on NA and 5-HT – variable within the group
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, extensive first pass effect  low and inconsistent BAV
Wide distribution and large Vd (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 Anticholinergic (atropine-like) due to M-blockade
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, palpitations,
Postural (orthostatic) hypotension + reflex tachycardia -blockade of adrenergic transmission (frequent in elderly)
Sedation, drowsiness(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
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 frequent
Precautions:
patient education (2-4 week delay in the effect is anticipated and that it is NOT a failure of medication)
therapy of concomitant anxiety/agitation

12. MonoAmine Oxidase Inhibitors (MAOI)
Principal mechanism of action:
Inhibition of intracellular enzyme MAO in CNS neurons (= decrease in degradation of catecholamines and serotonin).
antidepressant action - MAO-A enzyme isoform inhibition  increased cytoplasmic pool of monoamines leading among other(s) to spontaneous leakage of monoamines.
Effects in normal non-depressed subjects
they may increase psychomotor activity and euphoria + excitements (while TCA would cause only sedation and/or confusion)  risk of abuse!

13. MAOI drugs Irreversible non-selective inhibitors (hydrazides)
long lasting inhibition (up to 1-2 weeks)
phenelzine
tranylcypromine
Reversible Inhibitors of MAO-A (RIMA)
moclobemide
Big 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.

14. Adverse reactions and toxicity
Hypertension
Postural hypotension (in up to 1/3 patients)
CNS stimulation – tremor, excitement, insomnia, convulsions (overdose).
Weight gain (increased appetite)
Rare severe hepatotoxicity (hydrazine MAOI)

15. 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 food contain high amounts of tyramine (natural indirect sympathomimetic produced during fermentation),
Tyramin is normally metabolized by MAO in the gut and liver.
In depressed patients treated with MAOI,
MAO inibited in the CNS as well as in the periphery
bioavailability of tyramine is significantly higher
pharmacodynamic synergism between MAO and tyramin
 strikingly increased NA 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.

16. 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

17. 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 (SERT) 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, drug withdrawal

18. Most important SSRI
Fluoxetine
Fluvoxamine
Paroxetine
Sertraline
Citalopram
Enantioselective forms e.g. escitalopram (S-enantiomer)

19. Pharmacokinetics Good absorption after oral administration
Important biotransformation in the liver
CYP D6 and 2C19 isoforms (polymorphism  interindividual variability in the clinical effect) and active metabolites (e.g., fluoxetine)
Long half-lives of elimination(s)
fluoxetine (T1/2=50h) + 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.

20. Adverse effects
Relative improvement to other antidepressants (mostly mild)
GIT – nausea, vomiting, abdominal cramps, diarrhea (relatively frequent, higher doses?)
Headache
Sexual dysfunctions (loss of libido, erectile dysfunction…)
Restlessness (akathisia)
Insomnia and fatigue
Few patients experience an increase in anxiety or agitation during early treatment
Serotonin syndrome upon intoxication or drug interactions

21. Other and atypical antidepressants
Serotonin (5HT2A) Antagonists/Reuptake Inhibitors (SARI)
In depression with significant anxiety and sleep disturbances
trazodone - inh. select. SERT, sedative effects – antag. H1 and 1 and 2
Serotonin and Noradrenaline Reuptake Inhibitors (SNRI)
venlafaxine
pharmacodynamics like in TCA, however, improved profile of adverse reactions
Very effective, better remission rate than SSRI
Adverse reactions: nauzea, vertigo (both frequent and may improve), hypertension, manic reactions
Used in: depression and depression with anxiety, generalized anxiety disorders, social fobias, neuropathic pain
Noradrenaline and Dopamine Reuptake Inhibitors (NDRI)
bupropion – rather CNS activating effects (low sedation),
use: severe depression + smoking cessation treatment.
adverse reactions: insomnia, excitation, restlessness, lowers epilepsy threshold
Noradrenaline Reuptake Inhibitors (NaRI)
reboxetine – also rather activating, severe depression prophylaxis and treatment
Miscellaneous
St John´s 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)

22. 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)

23. Lithium Principle mechanism of action Pharmacokinetics
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)

24. Lithium – toxicity and adverse reactions
GIT: vomiting, profuse diarrhea
CNS: confusion, tremor, ataxia, convulsions, coma.
Heart: arrhythmias, hypotension
Kidney – long term treatment
Drug interactions:
thiazides – increased Li reabsorption  intoxication
TDM to reach desirable effects without risk of toxicity!
The range of plasma concentrations is narrow:
mmol/L (above 1.5 mmol/L toxic effects appear)