Assoc. Prof. Iv . Lambev www.medpharm-sofia.eu

1. Medical University of Sofia, Faculty of Medicine Department of Pharmacology and Toxicology • Antidepressants • Mood stabilizers • Psychostimulants • Nootropic drugs • CNS stimulants • (Abstract) Assoc. Prof. Iv. Lambev www.medpharm-sofia.eu

2. Depression is a heterogeneous disorder. A simplified classification based on presumed origin is as follows: (1) brief reactive or secondary depression (most common), occurring in response to real stimuli such as grief, illness, etc; (2) major depression (melancholic and recurrent depression) a genetically determined biochemical disorder manifested by an inability to experience ordinary pleasure or to cope with ordinary life events; (3)manic-depressive depression (depression associated with bipolar affective disorder) Pharmacologic treatment of depressions is very important, although a continuing role for electroconvulsive therapy for severe forms of life-threatening depression is also noted.

3. manic

4. Depression is one of the most common psychiatric disorders. At any given moment, about 3–5% of the population is depressed, and an estimated 10% of people may become depressed during their lives. The symptoms of depression are often subtle and unrecognized both by patients and by physicians. Patients with vague complaints that resist explanation as manifestations of somatic disorders and those who might be simplistically described as “neurotic” should be suspected of being depressed. Soon afterthe introduction of reserpine (1948), it became apparent that the drug could induce depression by inhibiting the neuronal storage of amine neurotransmitters 5-HT and NE. Reserpine-induced depression and depleted stores of amine neuro- transmitters. It was reasoned, depression must be associated with decreased functional amine-dependent synaptic transmission.

6. NA (noradrenaline) = NE (norepinephrine)

7. Rauwolfia serpentina • (a small indian shrub) • Reserpine • Ajmaline

8. Pathogenesis of depression • The idea that depression must be associated with decreased • functional amine-dependent synaptic transmission • provided the basis for amine hypothesis of depression. • By extension, drugs that increased amine function in appropriate synaptic areas would relieve depression. • The amine hypothesis has provided the major experimental models for the discovery of new antidepressants. • All currently available antidepressants, except bupropion, • are classified as having their primary actions on the • metabolism, reuptake, or selective receptor antagonism • of 5-HT, NA, or both.

9. (5-HT) (NE) (DA) The effects of DA, 5-HT and NE on the brain functions

10. Raised neurotransmitter concentrations produce immediate alterations in postsynaptic receptor activation, leading to changes in second messenger (intracellular) systems and to gradual modifications in cellular protein expression. Antidepressants increase a cyclic AMP response-element binding (CREB) protein which in turn is involved in regulating the transcription of genes that influence survival of other proteins including brain derived neurotrophic factor (BDNF) which exerts effects on neuronal growth. The role of BDNF in depression is supported by the observation that stress both reduces its expression and impairs neurogenesis.

12. The monoamine hypothesis of depression is an oversimplification(only deficieny of NA, 5-HT, and DA)of a complicated picture. Other systems that are implicated in the etiology of depression (and which provide potential targets for drug therapy) include the hypothalamo-pituitarythyroid axis and the hypothalamo-pituitary-adrenal axis (HPA). The finding that 50% of depressed patients have elevated plasma cortisol concentrations constitutes evidence that depression is associated with increased HPA drive.

14. Structural relationships between various tricyclic antidepressants (TCAs). Their structures are similar to phenothiazines.

15. Selective serotonin reuptake inhibitors (SSRIs).

16. Pharmacokinetics The antidepressants are generally well absorbed after oral administration. Steady-state plasma concentrations of TCAs show great individual variation but correlate with therapeutic effect. Antidepressants in general are inactivated princi- pally by metabolism by hepatic cytochrome P450 enzymes (2D6 and 3A4). Other cytochrome enzymes are CYP 1A2 inhibited by the SSRI fluvoxamine, and induced by cigarette smoking, caffeine and the atypical antipsychotics (clozapine and olanzapine).

17. Several of these drugs produce active metabolites which prolong their action (e.g. fluoxetine is metabolized to norfluoxetine, t1/2 200 h). The meta- bolic products of certain TCAs are antidepressants too, e.g. nortriptyline (from amitriptyline), desipramine (from imipramine). Half-lives of TCAs and SSRIs are long (> 15 h). Around 7% of the Caucasian population have very limited CYP 2D6 enzyme activity. Such “poor metabolizers” may find standard doses of tricyclic antidepressants intolerable and it is often worth starting at a very low dose.

18. Clinical indications The major indication is to treat depression, but a number of other uses have been established by clinical experience. Antidepressants may benefit most forms of anxiety disorder (panic disorder, generalized anxiety disorder, post-traumatic stress, obsessive-compulsive disorder, and social phobia), migraine. SSRIs are effective in milder cases of the eating disorder bulimia nervosa, particularly fluoxetine (in higher doses than are required for depression). Antidepressants appear to be ineffective in anorexia nervosa.

19. SSRIs (selective serotonin • reuptake inhibitors) • are used in: • panic disorders • chronic anxiety • depression • bulimia neurosa • (fluoxetine – in higher doses)

20. Schematic representation of the time course of panic treatments Adapted from Bennett and Brown (2003)

21. Mode of use The action of TCAs in ameliorating mood is usually absent in the first 2 weeks of therapy and at least 4 weeks must elapse to constitute an adequate trial. Where a minimal response is noted in this period, it is reasonable to extend the trial to 6 weeks to see if further benefit is achieved. Dose titration is often necessary. By contrast, patients may experience unwanted drug effects immediately on starting treatment (and they should be warned), but such symptoms often diminish with time. TCAs are given either in divided doses or, for the more sedative compounds, as a single evening dose.

22. SSRIs have advantages over tricyclics in simplicity of introduction and use. Dose titration is often unnecessary since the minimum therapeutic dose can usually be tolerated as a starting dose. Divided doses are not required and administration is by a single morning or evening dose. Patients commencing treatment on SSRIs are more likely to reach an effective dose than those starting on TCAs. Venlafaxine is licensed for treatment-resistant depression by gradual dose titration. There is some need for dose titration when using MAOIs.

23. Side effects of TCAs Anticholinergic (atropine-like): dry mouth, blurred vision, accommodation disturbances, increased ocularpressure, con- stipation, urinary retention, sweating, adynamic ileus (very rare). CNS: dizziness, tiredness, confusion, tremor,insomnia, seizures, exacerbation of psychotic symptoms. CVS: postural hypotension, sinus tachycardia, arrhythmia. Blood: leucopenia, agranulocytosis, thrombocytopenia, Haemolyticanaemia. Other ADRs: impairedrespiration,libido changes,tinnitus, GI complaints, liver functiondisturbances,increased body weight.

25. Precautions:close supervision, especially in early phaseof treatment (suicide risk of TCAs). The possibility of unmasking a latentpsychosis should be considered. A switch into amanic or hypomanic condition may occur (“switch process”). Caution should be exercised in CVD, history of urinary retention, narrow-angle glaucoma, and thyroid disease. Side-effects of SSRIs (mainly during the 1st and 2nd weeks of treatment): CNS:head- ache, restleness; CVS:bradycaria; GIT:nausea, diarrhoea The serotonin syndrome is a rare but dangerous complication with features restlessness, tremor, hуperthermia, convulsions, coma and death. Risk is increased by co-administration with MAOIs, the antimigraine drug sumatriptan, and St. John’s Wort.

27. Side-effects of MAOIs (Moclobemide) CNS: insomnia, restlessness, confusion, dizziness. CVS: arrhythmia, tachycardia, palpitations, high blood pressure. The following foods and beverages should be avoided– tyramine containing nutrition: maturated cheese (“cheese syndrome” – high blood pressure), broad beans, smoked or pickled fish, meat extractscontaining brewer's yeast, fermentedsausages (e.g. salami); red wine, sherry, beer and excessive amounts of alcohol.

28. Trazodone acts by antagonism of central presynaptic alpha-2-adrenoceptors. It is an option for depressed patients where heavy sedationis required. Trazodone also has the advantages of lacking antimuscarinic effects and being relatively safe in overdose. Males should be warned of the possibility of priapism (painful penile erections), due to the blockade of peripheral postsynaptic alpha-1-adrenoceptors. Mianserin has the advantages of lacking antimuscarinic effects too, but can cuases aplastic anaemia.

29. Agomelatine (Valdoxan®) is a melatonergic agonist (MT1- and MT2-receptors) and 5-HT2C antagonist. It has no effect on monoamine reuptake and no affinity for α, β adrenergic, histaminergic, cholinergic, dopaminergic and benzodiazepine receptors. Agomelatine is indicated for the treatment of major depressive episodes in adults. It not use in chlidren below 18 years of age due to a lack of data on safety and efficacy.

30. Many patients with mild to moderate depression are aware of the benefits of the herbal remedy St. John’s Wort.The major active antidepressive constituents are thought to behyperforin and hypericin. Some believe thathyperforin is the major constituent responsible forantidepressant activity. Itinhibits the reuptake of 5-HT, DA, and NA. Hyperforin also has affinity for GABA and glutamate receptors. Hypericum perforatum L.

31. St. John’s Wort Many patients with mild to moderate depression are aware of the benefits of the herbal remedy St. John’s Wort. The major active antidepressive constituents are thought to behyperfurin and hypericin. Some believe Thathyperfurin is the major constituent responsible for antidepressant activity.Itinhibits the reuptake of 5-HT, DA, and NA (NE). Hyperfurin also has affinity for GABA and glutamate receptors.

32. Use of St. John’s Wort is complicated by the lack of standardization of the ingredients. Those who wish to take St. John's Wort should be made aware that it may cause dry mouth, dizziness, sedation, GI disturbance and confusion. It induces hepatic CYP 1A2 and CYP 3A4 with the result that the plasma concentration and therapeutic efficacy of warfarin, oral contraceptives, some anticonvulsants,antipsychotics and HIV protease/reverse transcriptase inhibitors are reduced. Concomitant use of tryptophan and St. John’s Wort may cause serotoninergic effects including nausea and agitation.

33. Electroconvulsive therapy (ECT)involves the passage of a small electric charge across the brain by electrodes applied to the frontotemporal aspects of the scalp with the aim of inducing a tonic-clonic seizure. ECT requires the patient to be receiving a general anaesthetic. It may cause memory deficit although this is generally transient. ECT is usually reserved for psychiatric illness where pharmacotherapy has been unsuccessful for instance the severely depressed patient who has stopped eating or drinking. Modern-day ECT is a safe and effective alternative to pharmacotherapy and remains a first-line option in clinical circumstances where rapid, response is desired, when it can be life-saving.

34. Mood stabilizers In bipolar affective disorder patients suffer episodes of mania, hypomania and depression, classically with periods of normal mood in between. Manic episodes involve greatly elevated mood, often interspersed with periods of irritability or undue excitement, accompanied by biological symptoms (increased energy, restlessness, decreased need for sleep, increased sex drive), loss of social inhibitions, irresponsible behaviour and grandiosity. Psychotic features may be present, particularly disordered thinking, manifested by grandiose delusions and “flight of ideas” with rapid speech.

35. Hypomania is a less dramatic and dangerous presentation but retains the features of elation or irritability and the biological symptoms, abnormalities in speech and in social conduct to overfamiliarity and mild recklessness. Depressive episodes include depressive symptoms described before and may include psychotic features. Lithium salts are ineffective for prophylaxis of bipolar affective disorder in around 35% of patients and cause severe unwanted effects. The search for alternatives has produced drugs that are more famous as anticonvulsants (carbamazepine and sodium valproate, and possibly lamotrigine).

36. The main effect of lithium is probably to inhibit hydrolysis of inositol phosphate, so reducing the recycling of free inositol for synthesis of phosphatidylinositides. These intracellular molecules are part of the transmembrane signaling system that is important in regulating intracellullar calcium ion concentration, which subsequently affects neurotransmitter release. Other putative mechanisms involve the cyclic AMP “second messenger” system and monoaminergic and cholinergic neurotransmitters.

37. Action of lithium on the IP3 and DAG second-messenger system. The schematic diagram shows the synaptic membrane of a neuron. (PIP2 – phosphatidylinositol-4,5-bisphosphate; PLC – phospholipase-C; G – G-coupling protein). Result:activation of protein kinase C, mobilization of intracellular Ca2+, etc. Lithium, by inhibiting the recycling of inositol substrates, may cause depletion of the second-messenger source PIP2 and therefore reduce the release of IP3 and DAG.

38. The therapeutic plasma concentration is close to the toxic concentration (low therapeutic index). Lithium is a small ion that, given orally, is rapidly absorbed throughout the gut. High peak plasma concentrations are avoided by using sustained-release formulations which deliver the peak plasma lithium concentrations in 5 h. With chronic use the plasma t1/2 of lithium is 15–30 h. Lithium is usually given 12-hourly to avoid unnecessary fluctuation (peak and trough concentrations) and to maintain a plasma concentration just below the toxic level. A steady-state plasma concentration will be attained after about 5–6 days (i.e. 5 x t1/2).

39. Lithium carbonate is effective treatment in 75% of episodes of acute mania or hypomania. Because its therapeutic action takes 2–3 weeks to develop, lithium is generally used in combination with lorazepam or diazepam (or with a neuroleptics where there are also psychotic features). For prophylaxis, lithium is indicated when there have been two episodes of mood disturbance in two years.

40. Lithium is also used to augment the action of antidepressants in treatment-resistant depression. The difference between therapeutic and toxic doses is narrow and therapy must be guided by monitoring of the plasma concentration once a steady state is reached. Increments are made at weekly intervals until the concentration lies within the range of 0.4–1 mmol/L (maintenance at the lower level is preferred for elderly patients). The plasma concentration should be checked every 3 months. Thyroid function and renal function (plasma creatinine and electrolytes) should be measured before initiation and every 3 months during therapy.

41. Side-effects of Lithium CNS: ataxia, dysarthria, choreoathetoid disturbances, extrapyrimidal symptoms, confusion, tremor, epileptic seizures, spasms, stupor, sedation, lethargy. CVS: arrhythmia, hypertension, circulatory collapse. Other effects: weight increase, muscular hypotonia, anorexia, nausea, vomiting, thirst, rash etc.

42. The manic phase in bipolar affective disorder often requires treatment with neuroleptics (chlorpromazine, haloperidol), though lithium or valproic acid supplemented with high-potency benzodiazepines (eg, lorazepam or clonazepam) may suffice in milder cases. Recent controlled trials support the efficacy of monotherapy with atypical antipsychotics (olanzapine)in the acute phase (up to 4 weeks) of mania.

43. Psychostimulants Psychostimulants have predominant cortical action. Their psychic effects are more important than those on medullary vital centres. (1) Methylxanthines Three methylxanthines are pharmacologically important: caffeine, theophylline, and theobromine. All of them occur naturally in certain plants. Only caffeine is used as a CNS stimulant. It is widely consumed in the form of beverages, including as infusions or decoctions, derived from these plants.

44. Methylxanthines (purine alkaloids) Caffeine, Theophylline, Theobromine Coffea arabica(seeds) In an average cup of coffee: Caffeine 75 mg Theobroma cacao (cocoa) In an average cup of cocoa: Caffeine 4 mg Theobromine 200 mg Cola acuminata (Guru nuts) In 330 ml bottle of cola drink: Caffeine 50 mg Thea sinensis (leaves) In an average cup of tea: Caffeine 50 mg Theophylline 1 mg

45. Actions of methylxanthines They block adenosine-1-receptors. Adenosine acts as a local mediators in CNS, CVS and other systems. Adenosine contracts bronchial muscles, dilates cerebral blood vessels, depresses cardiac pacemaker and inhibits gastric secretions. Methylxanthines inhibit phosphodiesterase which degrades intracelullarly cAMP. Theophylline-containing preparations enhance cAMP accumulation. It results in bronchodilation, vasodilation and cardiac stimulation (including tachycardia). Caffeine and theophylline are CNS stimulants, primarily affect the higher centres. Caffeine (150 to 250 mg) produces a sense of wellbeing, alertness, beats boredom, alleviates fatigue; thinking becomes clear, improves performance and increases motor activity.

46. As a CNS stimulant caffeine is more active than theophylline. In higher doses caffeine causes nervousness, restlessness, panic, insomnia, and excitement. Still higher doses produces tremor, arrhythmia, delirium, and convulsions. Methylxanthines, especially caffeine, also stimulate medullary vagal, respiratory and vasomotor centres (analeptic effect). Vomiting in higher doses is due to both to gastric irritation and stimulation ofchemoreceptor trigger zone (CTZ). Methylxanthines directly stimulate the heart and increase force of myocardial contraction. They tend to increase heart rate by direct action, but also decrease it by vagal stimulation. Net effect is variable. Tachycardia is more common with theophylline.

47. Cardiac output is increased. This action is more marked in CHF patients. At high doses cardiac arrhythmias may be produced. Methylxanthines, especially theophylline, dilate systemic blood vessels, including coronaries. Cranial vessels are constricted by caffeine: this is one of the bases of its use in migraine. Effect of blood pressure is variable and unpredictable. Usually a rise in systolic and fall in diastolic BP is observed. Antiasthmatic (bronchodilatation) effect of theophylline is more potent then those of caffeine.

48. Caffeine >300 mg/d: 5–6 coffee cups daily (–) AC PD cAMP ATP 3’, 5’-AMP Hypercholesterolemia (+) (+) Cholesterol synthesis Lipolysis

49. Methylxanthines are mild diuretics. They act by inhibiting tubular reabsorption of Na+ and water. Theophylline and theobromine are more potent diuretics than caffeine. At high dose caffeine enhances the contractile power of skeletal muscle: it increases release of Ca2+ from sarcoplasmatic reticulum by direct action. In addition, caffeine facilitates neuromuscular transmission by increasing ACh release. Its central action relieves fatigue and increases muscular work. Methylxanthines enhance secretion of acid and pepsin in the stomach, even on parenteral application. They are gastric irritants– theophylline more than caffeine.

50. Caffeine is an alkaloid with pKb 0.8. It is rapidly absorbed after • oral administration. It is < 50% bound to plasma proteins. Its • t1/2 is 4 h. Caffeine is nearly completely metabolized in the liver by • demethylation and oxidation, and excreted in urine. Caffeine is • to be avoided in peptic ulcer patients. It is not contraindicated • in gout because it is not converted in the body to uric acid. • Moderate coffee drinking does not contribute to • development of hypertension. • Uses of caffeine • In analgesic drug combinations: caffeine benefits headache • probably by allaying fatigue and boredom. • Migraine attacks: in combination with ergotamine. • To counteract hypnotic overdose, but its value is doubtful, • better not to be used.