Clinical response time antidepressants

Various factors may account for the variability in response to neuroleptics. These include differences in the diagnostic criteria, concurrent administration of drugs which may affect the absorption and metabolism of the neuroleptics (e.g. tricyclic antidepressants), different times of blood sampling, and variations due to the different type of assay method used. In some cases, the failure to obtain consistent relationships between the plasma neuroleptic concentration and the clinical response may be explained by the contribution of active metabolites to the therapeutic effects. Thus chlorpromazine, thioridazine, levomepromazine (methotrime-prazine) and loxapine have active metabolites which reach peak plasma concentrations within the same range as those of the parent compounds. As these metabolites often have pharmacodynamic and pharmacokinetic activities which differ from those of the parent compound, it is essential to determine the plasma concentrations of both the parent compound and its metabolites in order to establish whether or not a relationship exists between the plasma concentration and the therapeutic outcome. 

A second important factor in nonresponse is insufficient duration of treatment. All antidepressant medications have a lag period between the time treatment starts and the time when a clinical response is readily... 

Education of patients about antidepressants has several facets. First, education about the biological aspects of depression is helpful, especially so that they do not view taking medication as a sign of moral weakness. Next, it is important to describe what to expect from the antidepressants what typical side effects are, that the medication is not habit forming, that a clinical response typically takes two to three weeks to be achieved, that side effects diminish over time, and that other medications can be tried if the first one does not work. For people taking MAOls, education about foods and medications to avoid is crucial. 

Caution is urged when switching from one antidepressant to another. It is important to remember that 3 to 4 weeks is usually required before a mood-elevating response is seen. A 6-week trial at a maximum dosage is considered an adequate trial. It is crucial to explain to the patient about the expected lag time before the onset of clinical response. Patients uneducated in this regard often fail to comply with their prescribed regimens. 

Depression may be due to a relative decrease in monoaminergic neurotransmission. In animal studies, tricyclic antidepressants initially block re-uptake of monoamines, resulting in higher neurotransmitter concentrations in the synaptic cleft. Over a period of time, the postsynaptic neuron responds to the chronic elevation of monoamines by expressing fewer receptors on the postsynaptic membrane. If indeed clinical response is due to receptor downregulation, then the hypothesis that depression is due to inadequate monoaminergic transmission would be unsatisfactory. It is unclear whether these mechanisms are responsible for relief from depression in humans. 

Fluoxetine (Prozac ) is a widely used antidepressant drug. In patients receiving daily doses of 20 or 40 mg, brain concentration continued to increase well after the clinical effects were evident (2 weeks), seemed to level off after about 6 to 10 months of treatment and was about 20 times the concentration in plasma. It thus appears that there is no correlation between brain concentration and clinical response. A combined in vivo and in vitro study on several patients showed that the single F resonance observed in vivo contains, in roughly equal proportion, both the drug and its active metabolite... 

These continuation trials tell a very different story from that told by relapse-prevention trials. They show that there is little difference between antidepressant and placebo even when the clinical trial is extended over a longer period of time. Across the eight continuation trials that have been published, 79 per cent of patients on placebo and 93 per cent of patients on active medication remained well throughout the treatment period. In these long-term studies, placebo treatment was 95 per cent as effective as drug treatment. The authors of a meta-analysis of these trials concluded that the widely held - and probably erroneous - belief that the placebo response in depression is short-lived appears to be based largely on intuition and perhaps wishful thinking .17... 

We do not use benzodiazepines as readily when treating GAD as we do when treating panic disorder. In comparison to those with panic disorder, most patients with GAD can more easily tolerate the delay in treatment response and even any transient exacerbation of anxiety associated with antidepressant therapy. Benzodiazepines are reserved for those who present with especially severe anxiety that necessitates more rapid relief than an antidepressant can afford and for those who do not achieve a satisfactory response to antidepressant or buspirone therapy. Due to the persistent nature of the anxiety experienced by patients with GAD, shortacting benzodiazepines such as alprazolam are not especially helpful unless dosed 3-4 times per day. Instead, we prefer long-acting agents such as clonazepam. When used to treat GAD, clonazepam should be started at a low dose (0.25-0.5 mg/day) and titrated to higher doses (1-4 mg/day) if clinically necessary. 

Most efficacy trials with reboxetine have so far only been published in review articles ( 178). Most of these articles did not have peer review and do not contain the full details concerning methodology or results. This fact limits the ability to accurately determine its relative efficacy and tolerability. In short-term (4 to 8 weeks), placebo-controlled clinical trials, reboxetine produced a response (defined as at least a 50% reduction in severity scores) in 56% to 74% of patients. These results were statistically superior to placebo in most studies. Reboxetine was also found to be as effective as imipramine and desipramine in four double-blind, randomized, active-controlled (but not placebo-controlled) studies involving more than 800 outpatients or inpatients with major depression. Reboxetine produced equivalent antidepressant response rates compared with fluoxetine in two clinical trials, one of which was also placebo-controlled. However, reboxetine was reported to have improved social motivation and behavior more than fluoxetine as assessed by the newly developed Social Adaptation Self-Evaluation Scale. In all of the studies, reboxetine had a similar time (i.e., 2 to 3 weeks) to onset of the antidepressant efficacy as do other antidepressants. 

It is unquestionable that current antipsychotic therapy is comparatively effective and at the same time disappointingly insufficient. These drugs can treat the symptoms of the disorder but certainly do not provide a cure. The great majority of patients will have between 20 and 50% reduction in symptom severity. Some will have marked improvement beyond these figures, although this is rare, and a small minority of patients will be entirely refractory to all forms of treatment currently available. Full results from antipsychotic therapy take considerable time (although initial effects on some positive symptoms can be seen in a few days). Whereas the effect of benzodiazepines on anxiety and sleep can be measured in hours, and that of antidepressants in weeks, the full impact of antipsychotic therapy is measured in months. A study by Robinson et al. (1999) showed that only 20% of patients responded after 4 weeks of treatment with conventional antipsychotics, whereas after 26 weeks the number of responders had grown to about 70%. Similar results were reported with clozapine treatment, where a response was observed in 40% of subjects after 4 weeks and in 60% of subjects by week 17 (Kane et al., 2001). Clinical observations clearly show that improvement in... 

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