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8-M. Bourini (46-52) 13/4/01 15:30 Page 46

Derlemeler/Reviews Psychopharmacological Treatment of Psychopharmacological Treatment of Depression

Michel Bourin, M.D., Ph.D.1

ABSTRACT: ÖZET: PSYCHOPHARMACOLOGICAL TREATMENT OF DEPRESSION DEPRESYONUN PS‹KOFARMAKOLOJ‹K TEDAV‹S‹ Correct diagnosis, cooperation of the patient, right dosage and Depresyonun farmakolojik tedavisinde do¤ru tan›, hastan›n the obsevation of the efficacy of the on the therapeutic tedaviyi kabulü, seçilen ilac›n uygun dozda kullan›lmas› ve has- improvement of the patient are always good means in reaching tan›n sonraki takip muayenelerinde kulland›¤› ilac›n iyilefltirici a successive treatment. As well as it is important for the clinican etkinli¤inin objektif bir flekilde görülmesi; tedavinin baflar›ya to have a precise knowledge of the disorder, it is as important eriflmesi için izlenecek iyi bir yoldur. Tedaviyi uygulayan kli- for him to acquire the knowledge on advantage, disadvantage nisyenin yeterli bir düzeyde hastal›k bilgisine sahip olmas› and the mechanism of the action of the drug he uses and the yan›nda; hastas› için seçece¤i ilac›n avantaj, dezavantaj ve etki- strategies for utilisation as well. In this article, phar- leflim mekanizmalar›n› içeren ürün bilgisini edinmifl olmas› ve macokinetic properties, , interaction and associative ilaç düzenleme stratejilerini iyi bilmesi gerekir. Bu yaz›da klasik properties of classic and new antidepresants are reviewed and ve yeni kuflak antidepresif ilaçlar›n farmakokinetik özellikleri, the prescription rules are summarised with the yan etkileri, etkileflim ve eflkullan›m özellikleri gözden geçiril- light of these reviewed data. mifl ve de¤erlendirilen bilgiler ›fl›¤›nda antidepresanlar› reçete etme kurallar› özetlenmifltir. Key words: depression, drug treatment, antidepressant Anahtar sözcükler: depresyon, ilaç tedavisi, antidepresan Bull Clin Psychopharmacol 2001;11:46-52 Klinik Psikofarmokoloji Bülteni 2001;11:46-52

An attentive clinical assessment may often permit Two pitfalls must be avoided: to distinguish the major depressive episodes from an - the unnecessary prescription to each patient isolated depressive symptom requiring anti-depres- presenting manifestations of asthenia or the pseudo- sant treatment (often transient), that doesn't justify depressive states, medicinal treatment (e.g. mourning). - the non-utilisation of antidepressant medicine The use of medicines is only justified: while prescribing , as far from improving 1) if the diagnosis of the depressive episode is the situation, risks the likelihood of aggravating the confirmed by a collection of clinical assessments disorder. (low self-esteem, guilt, slower psychomotor activity, If the correct product is chosen and adhered to , weight loss, sleep interruption...). one observes 70% efficacy. 2) if it is possible to obtain with the co-operation The prescription of an antidepressant therefore of the patient for an adequate dosage, an assess- requires: ment of 4 to 8 weeks necessary for the development - the precise knowledge of the illness of full efficacy. - the knowledge of the product (advantages, dis- 3) if a regular check-up of the patient occurs for advantage, supposed mechanisms of action) the assessment of the therapeutic benefits and - the knowledge of the strategy of utilisation and whether it is of interest to pursue or not the treat- association with anxiolytics or sedatives, which is ment during the phase of convalescents (4 months less often considered after the remission of symptoms). The patient may require emergency measures: I - hospitalisation, electroshock, e.g. due to suicidal risks. In 1950, in search of new antihistaminic mole-

1Professor of Psyhiatry; Pharm. D.; , EA Neurobiology of Anxiety and Depression - Faculty of Medicine, B.P. 53508 - 44035 NANTES Cedex 1

Yaz›flma Adresi / Address reprint requests to: Michel Bourin, EA Neurobiology of Anxiety and Depression - Faculty of Medicine, B.P. 53508 - 44035 NANTES Cedex 1 e-mail address: [email protected]

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M. Bourin

cules, chemists at the GEIGY laboratory in Bâle, syn- antidepressants, a reduction of the degradation of thesised the molecule , having a similar these amines, a blockade of the inhibitory feedback, structure to the antihistaminic . It an action at the second messenger level (probably failed the first antihistaminic pharmacological tests the common action of much antidepressants) as well and the product was set aside and forgotten. as post-synaptic action. It was believed for a long In 1952, the discovery of the multiple actions of time that the common effect of all anti-depressants ; immediately sent the pharmaceuti- was "down-regulation", i.e. the reduction of the cal industry into a spin and every business wanted to number of the central beta receptors during chronic have its own" neuroleptic ", but the SPECIA patents administration of anti-depressants, since this dis- were taken and it was difficult to copy the chlorpro- rupts down-regulation or appears about fifteen days mazine molecule. The existence of imipramine was after the beginning of administration. (2) It was sug- then remembered at the GEIGY laboratory and it gested as a rational explanation as to the activity of underwent new pharmacological tests only to reveal antidepressants, as the clinical effects were not man- again its neuroleptic inactivity. GEIGY persisted in ifested until after this time had elapsed. their search and confided in the assistance of a psy- Unfortunately, it has since been uncovered that anti- chiatrist (Kuhn) who prescribed imipramine in the depressants down-regulate more than just the beta same situations requiring chlorpromazine prescrip- adrenergic receptors, as the newer antidepressants tion, but he also found it lacked neuroleptic activity. are clinically active through the inhibition of the Here we admire the clinician’s persistence, as having . Even through the down-regula- noticed certain behavioural changes in patients, tion of the beta-receptors is observed with fluvox- retried the molecule in different situations and was amine, and ; this is not the case the first in 1957 to describe the antidepressant with and , however all SSRIs attributes of a chemical substance. (1) normalise the function and density of the 5-HT1 and These clinical results were confirmed in 5-HT2 receptors (see further on). Thus, one suppos- in 1959. Psychiatrists spoke of a chlorpromazine-like es that the common action of antidepressants can be medicine having a special effect on mood that they associated with the down-regulation of the seroton- qualified as thymoanaleptic. ergic receptors. Antidepressants may serve as media- The term thymoanaleptic defined by Delay repre- tors between the noradrenergic and sys- sents the main effect of these products; stimulate tems. Many hypotheses have recently been formulat- the mood when it is depressed, while not affecting ed. Indeed, animal studies have shown that tricyclic vigilance, specifically addressing depressive mood. In antidepressants can themselves interact with G-pro- a patient suffering from depression, antidepressants teins. (3) can surpass their goal and provoke an inversion of mood, either a simple euphoria or sometimes a real 1.2. OF TRICYCLIC ANTI- manic episode that requires an immediate withdraw- DEPRESSANTS al of treatment. This inversion of mood is more frequent if the The pharmacokinetics of are charac- patient presented some manic episodes before- terised by: hand (bipolar depression). Therapeutic activity - a generally long resorption (4-8 hrs.) partly due only appears after a minimum of 10 to 20 days of to a parasympatholytic effect that slows down gas- treatment and the secondary effects are numer- tric drainage ous. - a first pass effect of 40 to 70% depending on the tricyclic derivative 1.1. HYPOTHESES OF ACTION ON THE CENTRAL - a strong percentage binding of plasma protein NERVOUS SYSTEM with important inter-individual fluctuations for the liberated fraction, that may be pharmacologically The mechanism of action of the most frequently active prescribed anti-depressants is the inhibition of - a principal hepatic elimination with enterohep- monoamine reuptake, i.e. noradrenaline, serotonin atic cycles conferring the anti-depressants with long or . One also observes for the majority of half-lives with notable differences among individuals

Klinik Psikofarmakoloji Bülteni, Cilt: 11, Say›: 1, 2001 / Bulletin of Clinical Psychopharmacology, Vol: 11, N.: 1, 2001 47 8-M. Bourini (46-52) 13/4/01 15:30 Page 48

Psychopharmacological Treatment of Depression

and medicinal interactions the resorption of the poison (pumping of the stom- - a variable plasma equilibrium state between ach) or symptomatic treatment and sodium lactate subjects due to the inter-individual variations of perfusion and monitoring, reducing the death rate. plasma clearance (300 to 1200 ml/min.). (6) - at the end of 1-4 weeks a functional balanced 1.3.2 - Provoked by therapeutic doses concentration state is achieved between the antide- The individual's response to these medicines pressant and (which may be more or less varies from one patient to another. active). 4 types of incidents or accidents have been - they rapidly distribute quickly to all tissues and described. their peripheral action appears 1/2 hour after inges- a) Those associated with the nature of the treat- tion. ed illness - they undergo several transformations, in partic- It is the inherent suicidal risk of the treated illness ular a monodesmethylation; in some cases the mon- which is at its worst after a few days of anti-depres- odesmethyl derivative may then be more active than sant treatment (inversion of mood). Motor disinhibi- the dimethyl product. Other transformations include tion occurs prior to the disappearance of the psy- N-oxidation, followed by glycurocon- chiatric syndrome: suicide jugation leading to metabolite elimina- Co-prescription with Tercian® () is tion:40% of the dose is eliminated in the urine in 3 recommended, the association with days (≠ with M.A.O Is.), half-life of 30hrs and achiev- is controversial due to disinhibition. The inversion of ing an equilibrium state in 5-8 days. (4) mood and the appearance of a manic state is espe- In humans the principal antidepressant or seda- cially dangerous in ambulatory cases. Delirium may tive effect is dependent on the proportion of the N- appear in psychotic patients. desmethyl metabolite formed, however this b) Side effects linked to the central nervous sys- desmethylation not only presents important individ- tem ual differences from one individual to another, but The neurological manifestations are relatively fre- also in the same individual as a function of time e.g. quent but nevertheless less impressive than those of the desmethyl derivative of is inactive. neuroleptics: (5) - different types of (1/3 of cases): Plasma product and derivative concentrations. . subtle tremors of the tongue and hands It is necessary to verify plasma concentrations in (emotional type) case of therapeutic failure or to eliminate an atypi- . slow tremors at rest but without muscular cal metabolite: too weak/strong desmethylation. hypertonia . frequent dysarthria 1.3. SIDE EFFECTS AND TOXICOLOGY . the " dysarthria- " syndrome often disappears with a reduction of dosage 1.3.1 - Provoked by massive ingestion of strong - some convulsions may occur at the beginning doses (suicide) of treatment in subjects with a previous history of Cardiovascular toxicity of tricyclics is a major ele- (or withdrawal) ment: it is a dramatic and irreversible toxicity with: - sleep disturbance is difficult to judge as often - contraction disorders impairing left ventricular the patients suffer from . function - weight gain, especially for mole- - repolarisation disorders, widening the QRS cules such as and maprotiline. complex on ECG resulting in circulation problems, c) Side effects linked to the autonomous nervous particularly cerebral, of anoxic convulsion origins. system It is a serious and relatively frequent poisoning Problems are mostly due to muscarinic effects. (the risk of suicide being very high in patients receiv- - dry mouth ing this kind of treatment) and poses a problem for - tachycardia and are indicated by an the emergency services in the resuscitation of this ECG showing -like effects: prolongation of type of intoxication. Indeed, the toxicity is irre- QT, ECG surveillance is required especially if there is versible and the only efficient gesture is to prevent a previous history of cardiovascular problems

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M. Bourin

- gastrointestinal effects: , sickness and 3. (VIVALAN®) is a compound whose most often , aggravated by phenoth- structure is similar to that of which is a iazines or antiparkinson and resulting in a beta-blocker, however, viloxazine lacks propranolol's paralytic ileus properties. Even though viloxazine has a different - genito-urinary disturbances: retention of urine structure to the tricyclics, it possesses many pharma- and dysuria. In the aged male patient, a prominent cological analogies with these derivatives. It is a prostate can trigger an acute retention of urine weak enough inhibitor of noradrenaline reuptake, it - there is also a reduction of and erection may possess an indirect beta-mimetic action. loss Its central and peripheral activity is - ophthalmic adaptation mydriasa and paralysis weaker that of tricyclics and it causes a moderate are also due to anticholinergic action and closed and transient concentration increase of the cerebral angle is a definite contra-indication biogenic amines. - associated with an action on the sympathetic system is frequent (alpha adrenergic III - MONOAMINE OXYDASE INHIBITORS blockade) - night sweats are abundant , accompanied by For the , the aim was to hot flushes. create new molecules differing from the old MAOIs in at least two fundamental points: the selectivity 1.3.3 - INCIDENTS AND ACCIDENTS DUE TO (either for MAO-A or MAO-B) and the reversibility of ASSOCIATIONS the link associated to enzymatic inhibition. One dis- tinguishes 2 types of MAOIs: - definite contra-indications of association with the M.A.O.Is 1) NON-SELECTIVE MAOIs - often in the case of polymedication with other psychotropics, the relation between plasma concen- These are the older irreversible types represented tration and dosage is impossible to determine. by and iproniazide. Their efficacy is com- parable to that of the reference tricyclic anti-depres- II - PHARMACOLOGICAL PROPERTIES OF ATYPI- sants but they are never prescribed to begin with due CAL ANTIDEPRESSANTS (NON-MAOI – NON-TRI- to the fact of their difficult handling management. CYCLIC) (5) These products are reserved for depressive states resistant to tricyclic anti-depressants; in fact they are 1. (ATHYMIL®) a piperazoazepine, pos- rarely prescribed. sesses a tetracyclic structure. It doesn't modify the The side effects are essentially linked to the reuptake of the different amines; on the other hand, blockade of degradation (notably it increases the turn-over of noradrenaline without peripheral): orthostatic hypotensions are frequent, affecting those of serotonin and dopamine. It blocks sudden has been described, notably in presynaptic alpha 1 action. Pharmacological studies cases of ingestion of food containing in animals show that mianserin antagonises the (cheese effect).(7) A delay of fifteen days is required action of serotonin in many tissues, notably at the in cases of general anaesthesia. level of the blood vessels. It also possesses anti-his- tamine properties as well as a sedative action, prob- 2) MAOI-As ably due to its alpha antagonistic effect. Its central or peripheral anticholinergic effect is modest. These are specific inhibitors of monoamine oxi- 2. (STABLON®) possesses an effect on dase A. Food and medicinal interactions are consid- mood disorders categorising it between the sedative erably reduced optimising the handling and toler- and antidepressants. After a rapid and ance to these new MAOIs, principally complete resorption its distribution is associated (HUMORYL®) (MOCLAMINE®) and with a high protein binding (close to 94%). Hepatic befloxatone. The pharmacovigilance of these pro- metabolism occurs by beta-oxidation and N- ducts confirms their good acceptability at therapeutic desmethylation. doses.

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IV – SPECIFIC SEROTONIN REUPTAKE INHIBITORS have been described due to dosage decrease during (SSRIs) the secession of the treatment. The serotoninergic syndrome, often unrecog- These serotonergic antidepressants are well nised, justifies the immediate withdrawal of the developed due to their close efficacy to the tricyclics treatment. It is due to certain overdoses or interac- but with weak anticholinergic effects and absence of tions and can lead to hospitalisation or even death. cardiac toxicity. They are prescribed in disorders (8) A whole order of symptoms are associated with other than depression (panic disorder, obsessive the digestive system (diarrhoea), parasympathetic compulsive disorder etc.). system (sweats, thermal dysregulation, hypo- or hypertension), motors symptoms (myoclonia, 1. INDICATIONS tremors) and neuropsychiatric symptoms (confusion, agitation or even coma). For the major DSMIV depressive states the SSRIs are the most prescribed anti-depressants. Their first 3. INTERACTIONS preference utilisation is easily justifiable for poly- medicated patients, suffering cardiovascular SSRIs can interact with concomitant medication pathologies. prescription due to the following mechanisms: - Fluoxetine (PROZAC®): Its oral resorption is good, varies from 70-85% and it is Enzymatic hepatic inhibition: explaining the risk not modified by foods. Its half-life varies from 1-4 of interaction with tricyclic antidepressants, anticon- days and that of its metabolite, norfluoxetine, is of vulsants ( and valproic acid), antipsy- 7 days. Fluoxetine is prescribed at a dose of 20 chotics and oral anticoagulants. mg/day. Association with other serotoninergic products - Sertraline (ZOLOFT®): possesses a half-life of may risk serotoninergic syndrome. Also association around 24 hrs which allows a once daily dosage. The with MAOIs (even selective) and is bioavailability is 88%. Binding to plasma proteins is strongly contra-indicated. (8) 99%. Sertraline is metabolised by the cytochrome Electrolytic modifications: the SSRIs are suscepti- P450 iso- and results in the metabolite: ble to cause a hyponatremia and the concomitant , possessing little active. administration of diuretics increases this risk (care is Sertraline is prescribed at a dose of 50 mg/day. required when treating elderly patients). - Paroxetine (DEROXAT®): possesses a half-life of The SSRIs, even though slightly less active than on average 24 hours, binding to plasma proteins is tricyclic antidepressants in clinical studies, have high (95%). Metabolism results in 5 that proven to be sufficiently efficient to be used in pref- are all inactive. Paroxetine is prescribed at a dose of erence in most depression cases, however their 20-40 mg/day. efficacy has not yet been proven in elderly patients - Citalopram (SEROPRAM®): has an excellent over 75 years old. bioavailability approaching 100%. Its half life is 33 hours. The binding to plasma proteins is 50%. The V - NEW ANTIDEPRESSANTS main metabolite of citalopram is norcitalopram. - (FLOXYFRAL®):has a half-life of Also called dual-action antidepressants, due to around 16hrs. Its bioavailability is independent of the fact of their multiple synaptic impacts.(9) food intake. 1. (EFFEXOR®): this molecule simul- 2. SIDE EFFECTS taneously inhibits serotonin and noradrenaline reup- take. The metabolism of venlafaxine results in the They most often concern the digestive system, active metabolite ( O-desmethyl-venlafaxine) and with nausea, vomiting and to a lesser degree consti- two inactive metabolites. It lacks or hist- pation and anorexia. Insomnia has been described aminergic activity. Its side effects are simi- as well as headaches, occasional hyper-perspiration lar to those of the SSRIs. There exists a dose-relation and decrease of the libido. Withdrawal syndromes response i.e. while increasing the dose one increases

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the number of responses. VI - RULES OF PRESCRIBING ANTIDEPRESSANT MEDICINES 2. (NORSET®): this molecule acts simultaneously on noradrenergic and serotoninergic 1. around 30% of depressive states resist receptors. It directly potentialises noradrenergic chemotherapy, transmission while blocking central alpha-2 recep- 2. the prescription of an anti-depressant is only tors and increasing serotoninergic transmission, an element of the global therapeutic treatment (+ mediated by 5-HT1 receptors while blocking 5-HT2 understanding and quality psychotherapy support), and 5-HT3 receptors.(10) 3. all depressive state types can benefit from Due to its particular pharmacological profile mir- chemotherapy, tazepine lacks anticholinergic-, adrenergic- and 4. the tricyclics dominate in term of absolute serotoninergic-type side effects. The typically sero- efficacy, toninergic side effects such as nausea, vomiting, 5. three criteria guide the choice of an anti- diarrhoea and sleep interruption were less described depressant in groups treated by mirtazapine and they don't - the severity and semiologic aspect of the have any consequences on the vital prognosis of depression patients, even the most aged. Some arthrosis-like - age and the somatic state of the patient side effects can occur but disappear after treatment - prescription habits of the physician withdrawal. 6. an anti-depressant cure requires - an optimum dosage (150 mg/day for the tricyclics) 3. (IXEL®): is a serotonin and nora- - surveillance and secondary effect correction drenaline . The bioavailability of - association of non-systematic psychotropics milnacipran is 85%, not modified by food intake. - length of the treatment: at least 6 months for The half-life is short: 8 hrs and plasma protein bind- the first episode, 12 months for the second, ten ing is weak. Metabolism is hepatic and doesn't result months and more for beyond. in active metabolites. When prescribed in the adult, 7. to respect contra-indications for major depressive states, milnacipran is used at a - due to parasympathetic effects: closed angle dose of 100 mg/day (50 mg twice daily). The side glaucoma, prostate hypertrophy, cardiac insuffi- effects seen during clinical studies have only rarely ciency: history of cardiovascular problems heart resulted in the withdrawal of treatment. Dizziness, attack, rhythm problems, coronary inflamma- hot flushes and hyper-perspiration, vomiting, nausea tion for tricyclics and digestive-type signs have been reported. Less - MAOIs association: SSRIs frequently reported are dry mouth and constipation. Ambulatory treatment In exceptional cases a serotoninergic syndrome may - the mismanagement of the suicidal risk occur and this risk is augmented by the association - prudence in the progressive increase of doses of MAOIs. The observed overdoses never resulted in and frequent consultations. Not to prescribe death. No cardiotoxicity has been observed. large quantities of the medicine.

References:

1. Kuhn R (1958) The treatment of depressive states with 3. Bourin M and Baker GB (1996) Do G-proteins have a role in G22355 (imipramine hydrochloride). Am. J. Psychiat. antidepressant actions? Eur. Neuropsychopharmacol. 6:49-53 115:459-464 4. Coutts RT, Fang J, Bourin M and Baker GB (1998) 2. Vetulani J and Sulser F (1975) Action of various antidepres- Principles of with an emphasis on psy- sant treatment reduces reactivity of noradrenergic cyclic AMP- chiatric drugs. Neuromethods 33; Cell Neurobiology generating system in limbic forebrain. Nature 257:495-496 Techniques, Eds. AA Boulton, GB Baker and AN Bateson, Humana Press

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5. Rotzinger S, Bourin M, Akimoto Y, Coutts RT and Baker 8. Thase ME (1997) Do we really need all these new antide- GB (1999) Metabolism of some second and fourth gener- pressants? Weighing the options. J. Prac. Psychiat. Behav. ation antidepressants: , viloxazine, , Health 3:3-17 mianserin, maprotiline, , and ven- lafaxine. Cell. Mol. Neurobiol. 19(4):427-442 9. Feighner JP (1999) Mechanism of action of antidepres- sant . J. Clin. Psychiat. 60(Suppl) 4:4-11 6. Henry JA (1989) A fatal toxicity index for antidepressant poisoning. Acta. Psychiat. Scand. 80:37-45 10. Moller HJ and Volz HP (1996) Drug treatment of depres- sion in the 1990s. Drugs 52:625-638 7. Janicak PG, Davis JM, Preskorn SH et al (1997) Principles and practice of clinical psychopharmacology. 2nd edition. Baltimore, Md; Williams & Wilkins

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