Antidepressants onset

The time for antidepressant onset of effect in BN is unclear. In the absence of data, the definition of a therapeutic trial from the depression hterature (4 to 8 weeks at a therapeutic dose) should be used. Since the majority of subjects will not experience a complete remission, and there are few data on predictors of response or whether switching to another class will improve response, a clear and specific target should be stated initially. Eor example, will the medication be continued if the patient has a 50% reduction in binge-purge episodes, or if abstinence from such behavior is the ultimate therapeutic goal. Optimal duration of treatment after response is also poorly defined. Most clinicians will treat for 6 months to 1 year and then re-evaluate the need for ongoing treatment. The evidence is mixed as to whether any early benefit is sustained, hence the decision to continue treatment should be made based on both initial response and the maintenance of that benefit. If the symptoms return within a few months after the antidepressant is discontinued, then the treatment may need to be reinitiated. 

Antidepressant therapy is usually associated with a delay of up to about two to three weeks before the onset of a cleat beneficial effect. Therefore, it... 

The second-generation antidepressants, particularly RIMAs and SSRJs, are much less toxic ia overdose than the older TCAs and irreversible MAO inhibitors. However, similar to first-generation antidepressants, the therapeutic effect only becomes manifest after several weeks. Up to one-third of depressed patients are nonresponders. Ideally, an antidepressant would combine a more rapid onset of action with greater clinical efficacy and a higher responder rate, as well as even better tolerability. 

Future Outlook for Antidepressants. Third-generation antidepressants are expected to combine superior efficacy and improved safety, but are unlikely to reduce the onset of therapeutic action in depressed patients (179). Many dmgs in clinical development as antidepressive agents focus on estabhshed properties such as inhibition of serotonin, dopamine, and/or noradrenaline reuptake, agonistic or antagonistic action at various serotonin receptor subtypes, presynaptic tt2-adrenoceptor antagonism, or specific monoamine—oxidase type A inhibition. Examples include buspirone (3) (only... 

Some alicyclic 1,2-diamine derivatives have recently been shown to have interesting CNS properties. For example, eclanamine (34) is an antidepressant with a rapid onset of action. The reasons for its potency are not as yet clear but pharmacologists note that the drug desensitizes adrenergic alpha-2 receptors and antagonizes the actions of clonidine. The synthesis of eclanamine starts with attack of cyclopentene oxide (30) by dimethylamine (to give 31). This product is converted to the mesylate by reaction with sodium hydride followed by mesyl chloride. Attack of... 

The very slow onset of action and side effects which follow from the anticholinergic side effects characteristic of the tricyclic antidepressants has led to a continuing effort to find replacements from other structural classes which might thus be devoid of this defect. A series of alkoxy phenylpropylamines has been investigated extensively in this search for non-tricyclic antidepressants. The most recent analogue, tomoxetine (69), is accessible by the same route [15] used to prepare the earlier analogue, nisoxetine, in which methoxyl replaces the ortho methyl group. 

Procedures that have been suggested as models of depression and used to look for neurochemical changes that parallel the onset of the behavioural change, as well as to test how antidepressants affect the behaviour, are listed in Table 20.3. Those that have been used most, either as a drug screen or in research into the neurobiology of depression, are as follows. 

Patients with bipolar disorder have a high risk of suicide. Factors that increase that risk are early age at disease onset, high number of depressive episodes, comorbid alcohol abuse, personal history of antidepressant-induced mania, and family history of suicidal behavior.15 In those with bipolar disorder, 1 of 5 suicide attempts are lethal, in contrast to 1 of 10 to 1 of 20 in the general population. 

The onset of response to antidepressants in social anxiety disorder is delayed and may be as long as 8 to 12 weeks. Patients responding to medication should be continued on treatment for at least 1 year. 

Antidepressants have a delayed onset of antipanic effect, typically 4 weeks, with optimal response at 6 to 12 weeks. Reduction of anticipatory anxiety and phobic avoidance generally follows improvement in panic symptoms. PD patients are more likely to experience stimulant-like side effects than patients with depression, and they should be initiated on lower doses (Table 37-6) of antidepressant than those that are used for depression or other... 

Taylor, Matthew J., Nick Freemantle, John R. Geddes and Zubin Bhagwagar, Early Onset of Selective Serotonin Reuptake Inhibitor Antidepressant Action Systematic Review and Meta-Analysis , Archives of General Psychiatry 63 (2006) 1217-23... 

This belief was further supported by the evidence of a correlation between the clinical response and REM sleep suppression as well as a temporal relationship between the onset of clinical response and REM sleep suppression. However, some of the later studies suggested that REM sleep suppression is not necessary for the antidepressant action (Gillin 1983). For example, some studies show evidence of no change or even an increase in REM sleep with the treatment of depression (Gillin et al. 2001). Recently, Landolt Gillin (Landolt and Gillin 2002) have also demonstrated that the antidepressant response to phenelzine treatment does not depend on elimination of REM sleep or inhibition of slow wave activity in non-REM sleep. However, the generalization of some of these studies is limited because of their small sample size. 

Amphetamine Clinically used for narcolepsy (sudden day-time onset sleep) and Attention Deficit Hyperactivity Disorder (ADHD) formerly used as a short-term slimming agent, as an antidepressant and to boost athletic performance recreational use widespread tolerance develops readily highly addictive regular users suffer many health problems and a reduced life expectancy amphetamine psychosis may develop, with similar symptoms to acute paranoid schizophrenia. 

Approximately 30-40% of patients will not respond to a given antidepressant and 60-75% may fail to achieve complete remission [16]. Consequently, in its least restricted definition, treatment resistance could be detected in the majority of depressed patients under treatment. Moreover, prior treatment failure negatively influences the response to subsequent antidepressant treatment, decreasing the odds of treatment response by a factor of 15-20% for each failed treatment [17]. The delayed onset of symptom relief (which takes three to eight weeks to occur) and the presence of adverse drug reactions contribute significantly to low treatment compliance. 

Special situations of sudden-onset/sudden-resolution pain, especially along a nerve track, or neuralgias, may require an adjunct of an anticonvulsant and/or tricyclic antidepressant. 

BZs are second-line agents except when rapid response is essential. They should not be used as monotherapy in panic disorder patients with a history of depression or alcohol or drug abuse. BZs are often used concomitantly with antidepressants in the first weeks to offset the delay in onset of antipanic effects. 

Postsynaptic changes in receptor sensitivity. Studies of many antidepressants have demonstrated that desensitization or downregulation of NE or 5-HT1A receptors may relate to onset of antidepressant effects. 

A 6-week antidepressant trial at a maximum dosage is considered an adequate trial. Patients must be told about the expected lag time of 2 to 4 weeks before the onset of antidepressant effect. 

Considerable effort in the field of monoamine reuptake inhibitors is focused on improving antidepressant efficacy since 30-40% of patients do not respond to treatment with currently available agents [6,7], An additional major objective is to enhance the onset of action. Current antidepressants typically require 2-6 weeks of treatment before clinical efficacy is seen [6]. Clinical trials exploring augmentation strategies, in which a DA reuptake inhibitor or a dual NE/DA reuptake inhibitor is combined with an SSRI, have resulted in improved efficacy in depressed patients refractory to SSRI treatment alone [4,5]. The improved results from clinical trials such as these serve to justify the considerable focus on the development of inhibitors that simultaneously block the reuptake of 5-HT, NE and DA. 

Monoamine Oxidase inhibitors (MAOis). Developed in the 1950s, the MAOIs were the first class of antidepressants. Subsequently, in the 1960s, the MAOis were also found to be effective anxiolytics. Unlike benzodiazepines and barbiturates, the MAOis are not addictive however, their onset of action is delayed not by minutes or hours but by 3 weeks or more. 

Buspirone (Buspar). The first nonsedating, nonbenzodiazepine specifically introduced as an anxiolytic, buspirone is FDA approved for the treatment of GAD. This medication acts as a partial agonist at the postsynaptic serotonin (5HT)-1A receptor. Like the antidepressants, buspirone has a delayed onset of action and effectively relieves the intrapsychic symptoms of GAD. Devoid of the muscle-relaxing properties of benzodiazepines, buspirone does not as effectively relieve the physical symptoms of GAD. Buspirone is not effective in the treatment of depression. Furthermore, its utility for the treatment of anxiety disorders other than GAD appears to be limited. 

In an attempt to explain the reason for the delay in the onset of the therapeutic effect of antidepressants, which is clearly unrelated to the acute actions of these drugs on monoamine reuptake transporters or intracellular metabolizing enzymes, emphasis has moved away from the presynaptic mechanism governing the release of the monoamine transmitters to the adaptive changes that occur in pre- and postsynaptic receptors that govern the physiological expression of neurotransmitter function. 

In SUMMARY, irrespective of the specificity of the antidepressants following their acute administration, it can be speculated that a common feature of all these drugs is to correct the abnormality in neurotransmitter receptor function. Such an effect of chronic antidepressant treatment may parallel the time of onset of the therapeutic response and contribute to the receptor sensitivity hypothesis of depression and the common mode of action of antidepressants. 

The field of antidepressant research was revolutionized in the late 1980s by the introduction of selective serotonin reuptake inhibitors (SSRIs), exemplified by fluoxetine (9). In addition to their antidepressant action, SSRIs have also proven effective for a broad range of psychiatric illnesses, and, more importantly, they demonstrated an improved tolerability profile as compared to TCAs and MAOIs due to their increased selectivity. On the other hand, SSRIs proved inferior to TCAs and MAOIs in their reduced antidepressant effects, slower onset of action, lower remission rates, and decreased ability to control the physical symptoms associated with depression. 

Due to the frequent unwanted effects and, in case of tranylcypromine, the numerous and dangerous interactions MAO-inhibitors are more and more replaced by the much less problematic SSRIs. Compounds belonging to this group are citalopram, escitalopram, fluoxetine, paroxetine and sertraline. They are used clinically in the therapy of depression, bulimia and obsessive-compulsive disorders. All SSRIs show a slow onset of action (1-2 weeks). They may induce insomnia and weight loss. The antidepressant ven-lafaxine inhibits both, serotonin and noradrenaline re-uptake and might therefore additionally induce hypertension. 

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