2. •At the end of the lecture, students must be able to,
–Understand and explain the monoamine theory of depression.
–Understand on the types of depression from the aspect of pharmacological treatment.
–Classify the drugs for depression (unipolar)
–Describe the pharmacology of each drug (MOA, PA, uses, adverse effects, drug interactions)
–Describe the drug therapy of bipolar disorder.

3. •What is depression?
•Clinical features, types, theories and pathophysiology of depression.
•Classification of antidepressant drugs
•Pharmacology of drugs
•Drug therapy of bipolar disorder

4. •Depression is the most common of the affective disorders (disorder of mood).
•may range from a very mild condition, to severe (psychotic) depression accompanied by hallucinations and delusions.
•Worldwide, depression is a major cause of disability and premature death.
•In addition to the significant suicide risk, depressed individuals are more likely to die from other causes, such as heart disease or cancer.
•often associated with other psychiatric conditions including anxiety, eating disorders and drug addiction

5. •Emotional symptoms
– low mood, excessive rumination of negative thought, misery, apathy and pessimism
–low self-esteem: feelings of guilt, inadequacy and ugliness
–indecisiveness, loss of motivation
–loss of reward.
•Biological symptoms include:
–retardation of thought and action
–loss of libido
–sleep disturbance and loss of appetite.

6. •Two distinct types
–Unipolar depression, in which the mood changes are always in the same direction,
–Bipolar affective disorder, in which depression alternates with mania.

7. Bipolar depression
•less common
•oscillating depression and mania over a period of a few weeks.
•strong hereditary tendency
• 75% --- non-familial, (Neurotic)
• clearly associated with stressful life events,
• accompanied by symptoms of anxiety and agitation;
• this type is sometimes termed reactive depression.
• 25% ----- (endogenous depression) (psychotic)
• familial pattern,
• unrelated to obvious external stresses
Unipolar depression

8. •main biochemical theory of depression - monoamine hypothesis,
•first proposed in 1965,
•which states that depression is caused by a functional deficit of the monoamine transmitters, noradrenaline and 5-hydroxytryptamine (5- HT) at certain sites in the brain,
•while mania results from a functional excess

10. A.Acute anxiety with depression:
e.g. benzodiazepines (Separate Lecture)
–mild, neurotic depression, esp. with anxiety.
–Short-term for acute onset.
–not effective for long-term treatment of psychotic depression.
B. Antidepressants:
•for psychotic depression, severe neurotic depression; long- term treatment.

11. 1.Monoamine uptake inhibitors
1.tricyclic antidepressants,
2.selective serotonin reuptake inhibitors,
3.newer inhibitors of noradrenaline and 5-HT reuptake
2.Monoamine receptor antagonists
3.Monoamine oxidase (MAO) inhibitors

13. •inhibit active uptake of biogenic amines noradrenaline and 5-HT into their respective neurons,
•increasing their concentration in the synaptic cleft in the CNS and periphery.
•Inhibition of NA and 5-HT uptake is associated with antidepressant action
•antidepressant action develops after weeks

14. Pharmacological actions:
CNS:
–mood elevation of depressed patients (Use);
–may extend to excitement, hypomania, mania with sufficient dose; agitation,seizures (Unt)
–no mood elevation or euphoria, but causes anxiety in normal persons.
–lowers seizure threshold, convulsions in overdose (Unt)
–respiratory depression with overdose (Unt)
ANS:
–anticholinergic action  atropine-like effects (Unt)
–potentiates exogenous & endogenous noradrenaline, sympathomimetics (Unt)
CVS:
–orthostatic hypotension, sinus tachycardia; arrhythmias and cardiac conduction defect with overdose (Unt)

15. may be classified into those with:
(a) Marked sedation: suitable for anxious and agitated patients.***
- amitriptyline
- trimepramine
- doxepin
(b) Less sedation: suitable for withdrawn and apathetic patient*****
- imipramine - desipramine
- nortriptyline

16. •MOA
– SERT mediates the reuptake of serotonin into the presynaptic terminal; neuronal uptake is the primary process by which neurotransmission via 5-HT is terminated.
–SSRI blocks reuptake and results in enhanced and prolonged serotonergic neurotransmission.

17. •most commonly prescribed group of antidepressants
•Acute toxicity (especially cardiotoxicity) is less than that of MAOIs or TCAs, so overdose risk is reduced.
•SSRIs are less sedating and have fewer antimuscarinic side effects than the older TCAs.
•No food reactions,
•but dangerous 'serotonin reaction' (hyperthermia, muscle rigidity, cardiovascular collapse) can occur if given with MAOIs.
•overall antidepressant efficacy similar to TCA, less efficacious in more severe depression
•in general, SSRIs DO NOT: **** cause weight gain

18. Disadvantages:
•Mild side-effects: nervousness, restlessness, insomnia, anorexia, headache, diarrhoea
•Impair performance of skilled tasks, e.g. driving;
•sexual dysfunctions
•May produce withdrawal symptoms  needs tailing off
-Indication : better tolerated and safer in overdose than other classes,
should be considered first-line drugs for treating depression.

19. in general, SSRIs DO NOT: ****
- produce anticholinergic side-effects
- cause postural hypotension, or inhibit cardiac conduction
- precipitate seizures
- interfere with cognitive and psychomotor functions, or cause sedation
- cause weight gain; food and drug interactions

20. = Non-selective monoamine uptake inhibitors
= serotonin/noradrenaline reuptake inhibitors, or 'SNRIs‘
•Eg. venlafaxine, desvenlafaxine
•MOA & status
•Generally similar to tricyclic antidepressants, fewer side effects.
•Less risk of cardiac effects, so safer in overdose than tricyclic antidepressants.
•Can be used to treat other disorders: eg. anxiety disorder, neurpathic pain

22. •Mirtazapine
–Blocks α2 adrenoreceptors and 5-HT2C receptors,
–Block of α2 adrenoceptors will not only increase noradrenaline release but will also enhance 5-HT release
•Trazodone
–5-HT reuptake inhibition.

23. •What are MAOs?
enzymes involved in deamination (degradation) of monoamines which include NA and 5-HT
•Two sub-types:
–MAO-A, preferentially deaminates 5-HT and NA
–MAO-B, preferentially deaminates phenylethylamine and dopamine.
•Types of MAOI
1.Non selective MAOI
2.Selective MAOI

25. Nonselective MAOIs
•inactivate the enzymes irreversibly
•mood elevation in both normal and depressed patient
•effects last 2-3 weeks after discontinuation
Selective MAOIs: Meclobemide
•inhibits MAO-A selectively and reversibly
•effective antidepressant, except in severe cases
•lacks anticholinergic, sedative, psychomotor and cardiaovascular adverse effects of typical TCAs
Status:
•well tolerated alternative to TCAs in mild to moderate depression;
•especially suitable for elderly patients and those with heart disease.

26. Status:
•much less frequently used, because of
(i) Interactions:
- “cheese reaction” with food containing tyramine, dopamine etc., - cheese, beer, wines, pickled meat and fish, yeast extract  hypertensive crisis
- with TCAs  severe toxicity resembling atropine poisoning
- with many others including: (indirect sympathomimetic drugs)
cold & cough remedies, antiparkinsonian drugs, pethidine, reserpine, guanethidine etc.  synergistic, adverse interactions
(ii) Untoward effects (adverse reactions),
- which include: CNS stimulation, anticholinergic effects, lowered convulsive
threshold, weight gain, and hepatotoxicity.
** overall antidepressant efficacy similar to TCA, less efficacious in more severe depression

28. •Mild depression - non-drug measures, antidepressant drugs – used - if the response is poor.
•The use of antidepressant drugs is advisable in the treatment of moderate to severe depression.
•Different classes of antidepressant drugs have similar efficacy but different side effects.
•Choice of drug is based on individual aspects including concomitant disease (TCAs in particular have several indications) and treatment (MAOIs and TCAs cause important interactions), suicide risk and previous response to treatment.

29. •Other things being equal, an SSRI is preferred as these are usually better tolerated and are less dangerous in overdose.
•Antidepressant drugs take several weeks before taking effect, so decisions on dose increment or switching to another class should not be made precipitately.
•An effective regimen should be continued for at least 2 years.
•In urgent situations, specialist consideration - possible use of electroconvulsive therapy.
•Anxiolytic (e.g. benzodiazepine), or antipsychotic drugs are useful adjuncts in some patients.

30. •Important points for drug therapy:
–reviewed every 1 – 2 weeks at start of therapy
–continued for at least 4 weeks (6 weeks in elderly) before contemplating switch
–following remission, continue same dose for at least 6 months
(12 months for elderly, 2 years for recurrent depression)
–withdrawal symptoms if stopped suddenly after 8 weeks or more, (physical dependence);  needs tailing off (4 weeks or longer)
–at least 2 weeks gap in-between, when switching drugs

31. •neuropathic pain (e.g. amytriptyline, nortryptyline)
•anxiety disorders (e.g. SSRIs, venlafaxine, duloxetine)
•fibromyalgia (e.g. duloxetine, venlafaxine, SSRIs, TCAs)
•bipolar depression (e.g. fluoxetine)
•smoking cessation (e.g. buproprion)
•attention-deficit hyperactivity disorder.

32. Drug used
–lithium (mood stabilizer)
–several antiepileptic drugs, e.g. carbamazepine, valproate, lamotrogine
–some atypical antipsychotic drugs, e.g. olanzapine, risperidone.
MOA
–Lithium is a monovalent cation
–can mimic the role of Na+ in excitable tissues,
–able to permeate the voltage-gated Na+ channels that are responsible for action potential generation
–not pumped out by the Na+-K+-ATPase, and therefore tends to accumulate inside excitable cells, leading to a partial loss of intracellular K+, and depolarisation of the cell

33. •Narrow Therapeutic Index: requires frequent (or regular) monitoring of serum drug levels. (clinically effective at a plasma concentration of 0.5-1 mmol/l, and above 1.5 mmol/L)
•Na+ depletion reduces the rate of excretion by increasing the reabsorption of lithium by the proximal tubule, and thus increases the likelihood of toxicity. -- ***** low salt diet increases serum drug level of lithium.*****
The main toxic effects
•nausea, vomiting and diarrhoea, tremor
•renal effects:
polyuria --- resulting from inhibition of the action of antidiuretic hormone.
(nephrogenic Diabetes insipidus)
•thyroid enlargement, sometimes associated with hypothyroidism
•weight gain
•hair loss.

34. •Lithium
–classical drug.
–used in prophylaxis and treatment of mania, and in the prophylaxis of bipolar disorder.
–Points for lithium
–there is a narrow therapeutic window and long duration of action
–acute toxic effects include cerebellar effects, nephrogenic diabetes insipidus and renal failure
–dose must be adjusted according to the plasma concentration
–elimination is via the kidney and is reduced by proximal tubular reabsorption.
–Diuretics increase the activity of the reabsorptive mechanism and hence can precipitate lithium toxicity
–thyroid disorders occur during chronic use.
•Carbamazepine valproate and lamotrogine (sodium channel blockers with antiepileptic actions) are used for:
–the prophylaxis and treatment of manic episodes in patients with bipolar disorder
–the treatment of bipolar depression.
•Olanzapine, risperidone (atypical antipsychotic drugs) are used to treat mania.

35. 1.Monoamine uptake inhibitors
1.tricyclic antidepressants (imipramine, desipramine, amitriptyline)
2.selective serotonin reuptake inhibitors (fluoxetine, fluvoxamine)
3.newer inhibitors of noradrenaline and 5-HT reuptake (venlafaxine , desvenlafaxine, duloxetine)
4.NA reuptake inhibitor (bupropion)
2.Monoamine receptor antagonists (mirtazapine, trazodone)
3.Monoamine oxidase (MAO) inhibitors
phenelzine - non-selective with respect to the MAO-A and -B
subtypes.
MAO-A-selective inhibitors (e.g. moclobemide).

36. References
•Brunton, L. Chabner, B. Knollman, B. Goodman & Gilman’s Pharmacological Basis of Therapeutics. 12th Edition. United States: The McGraw-Hill Companies, Inc.
•Rang, HP, Dale, MM, Ritter, JM, Flower, RJ, Henderson, G (2012). Rang and Dale's Pharmacology. 7th ed. London: Elsevier Churchill Livingstone