Depression Symptoms Treatment

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1981

The first modern antidepressant drugs were developed in the 1950s. Initially drugs which were inhibitors of the enzyme monoamine oxidase (MAO) were discovered to have useful antidepressant properties and, several years later, a second and more important class of antidepressant compounds was discovered. Imipramine is the prototype of the latter category, known as the tricyclic antidepressants (TAD) and now much more extensively used than the MAO inhibitors. Through the years, an ever-increasing number of TADs has become available; however, most of the new drugs are analogues of existing compounds rather than completely new chemical entities. At this time three MAO inhibitors and ten TADs and related compounds are marketed in Canada, while several others are under investigation. Antidepressants marketed in Canada are listed in Table 1 by generic name and principal trademark; the optimum daily dosage range for office patients is also given. The introduction of each new antidepressant is accompanied by claims of advantages which are usually expressed in terms of a more rapid onset of action, less severe side effects and lower toxicity, especially cardiotoxicity. Although in clinical use these claims are often very difficult to evaluate, the many drugs available do allow selectivity in matching the pharmacological profile of an antidepressant with a patient’s condition and needs.

When to Use Antidepressants

Depression is a very frequent illness with a much higher prevalence in the community than indicated by the number of diagnosed and treated cases. Family doctors are likely to see depressions of less severe intensity and in an earlier phase of their course than psychiatrists. Since many such office patients present ‘masked depressions’ or ‘depressive equivalents’ where somatic symptoms overshadow the affective disturbance, the differential diagnosis of depression should be considered when certain patterns of physical symptoms are present, diagnostic investigation reveals no physical cause and symptomatic relief is not obtained with the usual remedies. The symptom complexes of anxiety, fatigue, chronic pain syndrome or gastrointestinal disturbances are the most frequent physical concomitants of an underlying depression.

A trial of treatment with antidepressants is indicated under the following circumstances: when the depression has lasted more than one or two weeks; when the patient’s sense of wellbeing and ability to perform to his usual level in customary family, social and vocational roles are impaired; when psychotherapy or treatment with sedatives, anti-anxiety agents or stimulants has not provided relief. Although depression is frequently associated with environmental stress, the presence of such stress does not preclude chemotherapy. Likewise, antidepressant chemotherapy and psychotherapy are mutually reinforcing and should be used jointly.

Clinical Pharmacology

Quickly absorbed after oral ingestion, TADs are highly lipid-soluble drugs, extensively metabolized by the liver and bound to the tissues, where their concentration is 10-20 times higher than in the blood. The essential effect of tricyclic metabolism is to form water-soluble compounds readily excreted in the urine. Tertiary amines like amitriptyline and imipramine are demethylated to secondary amines, nortriptyline and desipramine respectively, which retain clinical activity.

Blood Levels

People treated with identical doses of TAD develop markedly different blood levels of the drug. Since the blood concentration is more closely related to the biological action of the TAD than to the dose, it is possible to adjust the dose of a TAD until levels within a defined therapeutic range are attained.

Monitoring blood levels of TAD has been found clinically useful as therapeutic ranges have been established for several of these agents (Table 2). In general, the interpretation of blood level data is rather complex.

Metabolic Tests

Recently, it has been proposed that response to a specific antidepressant might be predicted by an initially high or low urinary excretion of MHPG, a norepinephrine metabolite. There is stronger evidence that the accuracy of diagnosis may be improved by using the dexamethasone suppression test. However, these are as yet experimental techniques and not applied routinely in clinical practice.

Which Antidepressant?

When starting treatment, the initial choice almost inevitably falls upon one of the TAD or related compounds. The use of MAO inhibitors is considerably restricted by their potential for serious side effects resulting from interactions with other drugs, foods and beverages. Although the risks associated with the MAO inhibitors have been overstated, the tricyclics are generally safer, more effective and thus more versatile.

There is no clearly evident overall superiority of one tricyclic over the others and in most patients therapeutically equivalent doses of different TADs will likely produce equal clinical results. In other words, amitriptyline and protriptyline are equally efficacious, but the latter is five times more potent on a milligram basis (see Table 1).

Imipramine and amitriptyline are the standard by which the other TADs are measured. Desipramine and nortriptyline are their respective active metabolites; a more rapid onset of action has been claimed but not always seen. Amitriptyline has the strongest anticholinergic action of the TADs and desipramine the weakest, with the other compounds in an intermediate position. Protriptyline and desipramine have the most pronounced stimulant action. Doxepin appears to be somewhat less cardiotoxic than the other TADs; along with trimipramine, its antidepressant effect does not appear to be as powerful as that of the earlier compounds. Maprotiline has a novel tetracyclic structure but is otherwise comparable to the other secondary amines. Amoxapine, the newest product, requires higher dosage than the others and has a structural affinity to the antipsychotic drug loxapine. Clomipramine has been found to have a therapeutic effect on obsessive-compulsive disorders apparently independent of its antidepressant action.

In general, patients incur the lowest costs if older preparations are prescribed generically, in the highest strength tablet compatible with the dosage schedule.

Clinical Use

A particular antidepressant should be selected on the basis of the physician’s personal experience with the consistent use of several of these drugs. The relative chances for various side effects with the different drugs should also be weighed. The labels affixed to depression such as reactive, endogenous, neurotic, psychotic, masked, etc., should not be relied upon for guidance in selecting a drug. Factors such as the physician’s experience with one or the other drug, the patient’s age and cardiac status, and personal or family history of response to previous antidepressant treatment are much more important. If the patient or a blood relative has responded favorably to a given antidepressant, the same agent should be used again.

Before starting treatment it is usually not necessary to perform a complex medical examination in younger and healthy individuals. Elderly depressed patients are at much greater risk of toxic effects and with such patients the status of the cardiovascular, cerebrovascular, urinary and ophthalmologic systems should be established. While TADs are not recommended for children under 12 years, imipramine in a bedtime dose of 25-75 mg has been used in young children to treat enuresis and school phobias.

Principles of Dosage

Some TADs are available in inject-able forms, but these are rarely used. A typical oral daily starting dose for a healthy adult might be 50-75 mg imipramine (or equivalent) prescribed as 25 mg bid or tid. The amount is usually increased by 25 or 50 mg every day until a dose of 100-200 mg a day is attained. Dose increments are prescribed according to the patient’s tolerance of the medication, incidence and severity of side effects and clinical response. Doses above 200 mg a day of imipramine (or equivalent) are associated with an increased risk of toxi-city and are best reserved for carefully supervised hospital patients.

The timing of doses through the day is important. Maximum doses should be achieved gradually. Since the half-lives of the antidepressants are sufficiently long, sustained-release formulations usually confer no special advantage. It is preferable to use the bulk of the daily dose at bedtime for convenience, to improve compliance and to exploit any sedative effect. When initiating treatment or when large doses of an antidepressant are used, divided doses should be used to minimize the anticholinergic and cardiotoxic actions of these drugs.

Because all the antidepressants have a limited margin of safety, it is unwise to dispense more than a week’s supply to a depressed and possibly suicidal outpatient. Suicide risk should be assessed and noted for each patient. Patients’ family members should be asked to help supervise the drug treatment. The drug should be kept out of the reach of children and in a securely closed container.

As far as possible, antidepressants should be the only drug administered to a patient, both in the interest of reducing the burden of chemical toxicity and to evaluate treatment response without having to consider the interactional influence of other medications. If it is necessary to control anxiety or insomnia, use of a benzodiazepine (diazepam, lorazepam, flurazepam, nitrazepam, etc.) is preferable.

How Long to Treat?

With all antidepressants there may be a delay in the onset of antidepressant effect, typically at least a week and sometimes up to three or four weeks. However, in many patients, objective signs of improvement may be observable within the first week— although the patient may be the last to acknowledge this. If no improvement is evident after three or four weeks and a full therapeutic dose has been reached, there is little likelihood that changing to another tricyclic or further increasing the dose will help. Since the main alternatives are then to try an MAO inhibitor or ECT, or to review the diagnosis, referral to a specialist is opportune.

Concerning duration of treatment, it is appropriate to continue at 100-150 mg of imipramine (or equivalent) for at least three months and then to decrease the dose gradually by 25 mg or 50 mg each week while observing for the possible breakthrough of depressive symptoms. In severe depression or in patients with a prior history of frequently recurring depression it is best to continue the treatment for a year or more. Although antidepressants have been administered for several years for the prophylaxis of recurrent depressions without apparent ill-effects, the efficacy and safety of indefinitely prolonged antidepressant therapy are not fully established. Lithium prophylaxis has been reported to be as successful in preventing depressive recurrences as longterm treatment with imipramine.

Side Effects and Toxicity

There is a low margin of safety between therapeutic and toxic doses of TADs. The most common side effects are extensions of the TAD’s pharma-cologic activities, foremost among which is the anticholinergic action responsible for the symptoms of dry mouth, sweating and impaired accommodation. These problems are usually more annoying than dangerous and can be managed by simple means such as mouthwashes or reading glasses. Some degree of tolerance to the side effects usually develops.

Among the more serious effects are the induction of glaucoma, paralytic ileus and urinary retention. Extra caution is thus required in elderly patients and men with hypertrophy of the prostate. Cardiac toxicity is a serious consequence of the anticholinergic and quinidine-like properties of the TAD and is to be expected in cases of acute over dosage or in sensitive individuals. Antidepressants must be used in lower doses and with great caution in elderly persons at risk for myocardial infarction and stroke. ECT modified by general anesthesia and muscle relaxation is as safe or safer than antidepressants for the treatment of severe depressions in the elderly or infirm.

The untoward CNS effects range from restlessness or insomnia to a toxic organic psychosis resembling atropine poisoning. Since TADs lower the seizure threshold, increased doses of anticonvulsants may be required.

The tricyclic antidepressants are a common choice for overdose. Acute doses of a few hundred mg of imipramine (or equivalent) have been severely toxic in adults as well as in children. Acute doses above 1000 mg are almost invariably very toxic and acute doses in excess of 2000 mg are often fatal. TADs pass the placental barrier and if used in pregnancy the balance of potential risk and benefit must be carefully weighed. In lactation, levels of antidepressants reaching breast milk and the infant’s plasma are minute, but cessation of breast-feeding is recommended.

Antidepressants and Antihypertensives

It is difficult to manage depression and hypertension in the same patient because of drug interactions. Depression may be associated with the use of several antihypertensive agents, notably reserpine and alphamethyldopa (Aldomet). Guanethidine (Ismelin) should not be used with any of the TADs, which nullify its antihypertensive action by blocking guanethidine uptake into the post-ganglionic sympathetic nerve fibers. Diuretics, beta blockers or smooth-muscle relaxants may be used with TADs.

Résumé

(French Language)

La dépression est une maladie paralysante qui n’est pas toujours diagnostiquée ni traitée. Les antidépresseurs sont un traitement spécifique pour cette condition mais leur utilisation demande beaucoup de jugement, de savoir et d’habilité. De nombreux médicaments sont disponibles mais à part quelques exceptions, à doses égales, il n’existe pas de différence substantielle dans leur efficacité totale. Le médecin se sert de son jugement clinique pour en recommander un plus que l’autre. De toute façon, les médecins doivent devenir complètement familiers avec plusieurs de ces agents. Un traitement d’essai demande des doses thérapeutiques durant trois à quatre semaines au moins. Ces médicaments ont une faible marge de sécurité; il y a du dager spécialement pour les gens âgés à cause des effets secondaires cardiaques, anticholinergiques et neurologiques. On décide empiriquement de la durée du traitement. Traiter avec succès une dépression par chimiothérapie est une des expériences les plus gratifiantes en médecine.