Beyond Antidepressants

Experience with the SSRls predicts that as therapeutic actions of selective NRIs expand beyond antidepressant actions, the doses of drug, onsets of action, degrees of efficacy, and tolerability profiles may differ from one therapeutic use to another (Table 6-7 and 6—8). 

Berton O, Nestler EJ (2006) New approaches to antidepressant drag discovery beyond monoamines. Nat Rev Neurosci 7 137-151... 

While such models of depression are quite useful in conceptualizing the mechanisms behind antidepressant activity, they are assuredly an oversimplification of the actual pathophysiologic process of the disorder. Depression probably involves a complex dysregulation of monoamine systems, and these systems, in turn, modulate and are modulated by other neurobio-logic systems. Thus, the underlying cause of depression may well extend beyond dysfunction of the monoamine system.10... 

In the decade that has passed since our article was published, the dust has settled around the issue of meta-analysis. It is no longer considered a controversial procedure. Meta-analyses of clinical trials are now routinely published in all of the top medical journals, and the National Institute for Health and Clinical Excellence (NICE), which publishes the treatment guidelines that are used by the NHS, crafts recommendations on the basis of meta-analyses that it conducts. Nevertheless, the editors were right about our article being controversial. Although some scholars in the field were persuaded by our analyses, others were sceptical, to put it mildly.2 The sceptics knew that antidepressants worked - if we had found otherwise, we must have done something wrong. Certainly there were other clinical trials of antidepressants beyond those that we had included in our analyses. Surely an analysis of those studies would point to a different conclusion. 

The TCAs are the only antidepressant class in which effectiveness is dependent on serum level. Attainment of the minimal therapeutic level is typically required for effectiveness. Exceeding the maximum treatment level usually provides no additional benefit and risks toxicity. Unique in this regard is nortriptyline, which is the only TCA with a therapeutic window. This means that beyond the maximum therapeutic level of 150ng/mL nortriptyline not only risks toxicity but is actually less effective at treating depression. Please refer to Table 3.9 for a summary of dosing guidelines and therapeutic levels. 

Wachtel, H. and Schneider, H.H. (1986) Rolipram, a novel antidepressant drug, reverses the hypothermia and hypokinesia of monoamine-depleted mice by an action beyond postsynaptic monoamine receptors. Neuropharmacology 25(10) 1119-1169. 

In the treatment of children and adolescents with anxiety disorders clinicians have a wide variety of pharmacologic options beyond the antidepressants (Shader and Greenblatt, 1995 Lydiard et ah, 1996 Riddle et ah, 1999). The benzodiazepines (BZs), with their favorable safety profile and quick onset of action, are attractive alternatives for the treatment of acute anxiety. While the clinical effectiveness of buspirone has not been proven in children, buspirone is used alone or in combination with other drugs in the treatment of anxiety disorders. The antihistamines are often used to treat insomnia and may reduce acute mild agitation. Zolpidem (Ambien) is occasionally used for its sedative properties. This chapter reviews the structure, proposed mechanisms of action, pharmacodynamic principles, and pharmacokinetic principles of these drugs. 

In 1995, Bramble published a study on the prescription frequency of antidepressants by British child psychiatrists (Bramble, 1995). A brief postal questionnaire was circulated to 350 members of the British Royal College of Psychiatrists, Child and Adolescent Psychiatry Specialist Sections. There was a 71% response rate, and 85% of the 238 respondents had employed antidepressants, the most popular of these being amitriptyline and imipramine. Nearly one-third of the psychiatrists at that time used neuroagents occasionally, and the SSRIs were used only very rarely. The antidepressant medication was used for a wide range of child and adolescent disorders beyond those of depression and nocturnal enuresis. Approximately 20% of the prescriptions were given for ADHD (hyperkinetic disorder), conduct disorder, and a few cases of autistic disorder. Clomipramine was apparently given for OCD. On the basis of these 1994 data. Bramble concluded that British child psychiatrists tend to use antidepressant medication far less often than American psychiatrists. 

Changing Targets of Antidepressant Therapy Serotonin and Beyond... 

O ver the past 10-15 years, much of the discussion of new antidepressant action has centered on serotonin (5-hydroxytryptamine [5-HT]). For a time, this caused other possible mechanisms to be neglected to some extent. It is appropriate to review the limitations of the serotonergic approach and examine what might lie beyond serotonin for the treatment of depression. 

As other indications are sought for the SSRls, it is clear that their action extends beyond depression, dysthymia, and the anxiety disorders, and the broad spectrum of therapeutic action of these antidepressants becomes apparent. For example, based on the evidence from placebo-controlled studies [A. Wood 1993], fluoxetine has been licensed in Europe for the treatment of bulimia, and several SSRls are reported to be effective in the treatment of premenstrual syndrome. 

In this chapter, we review the pharmacology of several selective serotonin reuptake inhibitors [SSRIs] and other drugs that act on the serotonergic system. That these developments have enhanced safety and tolerability is now beyond dispute, but it is also clear that these agents are no more effective than the old-style tricyclic antidepressants [TCAs]. [For a comprehensive discussion of serotonergic medication, see Montgomery, Chapter 12, in this volume.] Here, several compounds are discussed in detail. 

In summary then, the first stage of valid treatment resistance can be defined as when the patient fails to respond to a trial of an antidepressant for at least 6 weeks, meeting the dosing requirements as outlined above. Beyond this, little consensus exists on how to define further stages of TRD and/or treatment adequacy. Some researchers have leaned on the number of prior... 

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