Antidepressants ineffectiveness

Selected for clinical trials as a compound to calm agitated patients, imipramine was relatively ineffective. However, it was observed to be effective in the treatment of certain depressed patients (38). Early studies on the mechanism of action showed that imipramine potentiates the effects of the catecholamines, primarily norepinephrine. This finding, along with other evidence, led to the hypothesis that the compound exerts its antidepressant effects by elevating norepinephrine levels at central adrenergic synapses. Subsequent studies have shown that the compound is a potent inhibitor of norepinephrine reuptake and, to a lesser extent, the uptake of serotonin, thus fitting the hypothesis that had been developed to explain the antidepressant actions ofMAOIs. 

This behavioural syndrome, rather emotively called learned helplessness", is widely believed to share many features of depression, not least because both culminate in psychomotor retardation and both are linked with experience of uncontrollable, unpredictable stress. Whether or not learned helplessness really is an analogue of depression remains controversial (Maier 1993). Nevertheless, escape deficits in rats are prevented by pretreatment with antidepressants from different generic groups. Other psychotropic agents, such as CNS stimulants and neuroleptics, are generally ineffective. 

The tricyclic antidepressants (TCAs) derive their name from their three-ringed molecular structure (Fig. 20.3) and emerged, in 1958, from a search for better neuroleptics than chlopromazine among the phenothiazines. The prototype, imipramine, turned out to be ineffective in treating the positive symptoms experienced by schizophrenics but it did relieve their depression (negative symptoms). In fact, imipramine is still the standard agent against which novel antidepressants are compared in clinical trials. 

Although the therapeutic effectiveness of antidepressants seemed astonishing 40 years ago and still seems indisputable to many people today, it is, in fact, an illusion. As I have shown earlier in this book, the difference between the effects of antidepressants and placebos is clinically insignificant, despite clinical-trial methods that ought to enhance it. But strangely enough, it is not the ineffectiveness of antidepressants that seals the fate of the chemical-imbalance theory. Rather, it is their effectiveness. The problem is that too many different types of antidepressants work too well for the theory to make physiological sense. 

Brown, Walter A., Are Antidepressants as Ineffective as They Look , Prevention Treatment, no. 26 (2002) http / /www.joumals.apa.org/ prevention / volumes / pre0050026c.html... 

Finally, a single open label trial of bupropion, a novel antidepressant with an obscure mechanism, found it helpful for depressive symptoms in PTSD patients but largely ineffective for the core symptoms of PTSD itself. 

The so-called atypical antidepressants such as venlafaxine and bupropion can be tried, but their safety and efficacy in treating patients with dementia have not been well studied. The older tricyclic antidepressants and monoamine oxidase inhibitors are not tolerated well by demented patients and should be avoided. Two possible exceptions are nortriptyline (Pamelor) and desipramine (Norpramin), but even these should be tried only after the newer antidepressants have proved ineffective. 

Chronic Agitation. For chronic agitation with physical aggression, sodium divalproex is the preferred treatment. If divalproex is ineffective, haloperidol or an atypical antipsychotic can be added or snbstituted. Other options include trazodone, carbamazepine, and SSRI antidepressants. 

Pharmacology Cyclobenzaprine, structurally related to the tricyclic antidepressants (TCAs), relieves skeletal muscle spasm of local origin without interfering with muscle function. It is ineffective in muscle spasm caused by CNS disease. The net effect is a reduction of tonic somatic motor activity, influencing both gamma and alpha motor systems. 

As with prescription antidepressants, there is a 2- or 3-week lag in onset of action. If side effects are marked, or if at 6 to 8 weeks Hypericum is deemed to be ineffective, the patient can be weaned off and another treatment considered. Unfortunately, there are no data about washout periods following discontinuation of St. John s wort. A conservative approach is to wait 2 weeks after ceasing St. John s wort before commencing another agent. 

It is likely that depression and anxiety disorders are associated with problems in several brain systems, and, indeed, different drugs appear to be effective in different people. Even though SSRIs are currently the first choice of drugs for treating many anxiety disorders, other classes of antidepressants are tried if the SSRIs prove ineffective. 

Several preliminary lines of research have started to suggest that antidepressants, once considered ineffective in generalized anxiety disorder, may be very efficacious [Gorman and Kent 1999]. In particular, venlafaxine has been effective in treating generalized anxiety disorder in both open-label and double-blind trials, and imipramine and paroxetine were as effective as a benzodiazepine in the long-term treatment of generalized anxiety disorder. 

ECT is an effective option even in patients with PMD who do not respond to antidepressants alone, an antipsychotic alone, or the combination of an antidepressant with an antipsychotic. However, unilateral ECT treatments may be ineffective. 

It is well established that monotherapy with various antidepressants or mood stabilizers is relatively ineffective (i.e., they are necessary but not sufficient) for treating mood disorders with associated psychosis. Thus, psychotically depressed patients are best managed with a combination of antipsychotic-antidepressant or with electroconvulsive therapy. Although antipsychotics have a more rapid onset of action than lithium in an acute manic episode, we are unaware of clinical trials that examine the differential effect of antipsychotics or lithium for nonpsychotic versus psychotic mania. This topic is discussed further in... 

These older antidepressants have a therapeutic range that is bound on the lower end by lack of efficacy and on the upper end by risk of serious toxicity. These drugs also have substantial interindividual variability in drug metabolism so that ineffective concentrations can develop in some patients on the usual dose and toxic concentrations can develop in others. For that reason, TDM is a standard of care issue when using TCAs to treat clinical depression ( 325). 

As a results of these studies, clinicians have proposed that switching to reboxetine or bupropion might a useful strategy given that these antidepressants share the ability with desipramine and imipramine to block NE uptake. Nevertheless, only one small open label study has been done to test this possibility ( 365). If bupropion is to be used in patients switched from an ineffective trial of fluoxetine, the dose should be kept low for several weeks to allow for the clearance of fluoxetine and norfluoxetine. Case reports indicate that fluoxetine can elevate levels of the active metabolites of bupropion, which, in turn, could mediate an increase risk of adverse effects (366). 

Available evidence indicates that systematic desensitization and in vivo exposure are the most effective treatment methods available. Pharmacological treatment has not been well investigated, but studies involving antidepressants suggest that TCAs and MAOIs are ineffective ( 85, 86 and 87). In addition, three studies suggest that sedative-hypnotic anxiolytics may undermine the behavioral treatment of specific phobias (88, 89 and 90). In another study, volunteers with animal phobias were exposed to their phobic object 1.5 hours after administration of either tolamolol, diazepam, or placebo in a double-blind crossover design. Tolamolol abolished the stress-induced tachycardia but had no beneficial behavioral or subjective effects ( 91). 

Until the 1980s, the BZDs were considered ineffective in the treatment of PD. Early controlled studies with the triazolobenzodiazepine alprazolam, however, demonstrated its antipanic properties. To achieve this benefit, this agent must often be given in higher doses (4 to 10 mg per day) than when given as an anxiolytic. Although alprazolam usually produces its therapeutic effect during the first week, antidepressants may take several weeks. 

Flistrionic personality disorder is similar to the syndrome that Liebowitz and Klein ( 259) have termed hysteroid dysphoria or atypical depression. MAOIs have proven to be very helpful in this condition and these data are reviewed in Chapter 7. As noted earlier, Rifkin et al. (242) also investigated the effects of antidepressants in patients with emotionally unstable personalities, a syndrome characterized by excitability and ineffectiveness when confronted with minor stress. This syndrome is primarily found in female adolescents whose moods consist of the following ... 

Five cases (ages 36, 48, 48 and 60 and one unknown three males and two females) reported intermittent ineffectiveness with sertraline, including complaints of does not seem to be working, anxiety attack, or worsening depression. In four cases, symptoms occurred after sertraline was added to the continuing St. John s wort therapy. In contrast to reports with other antidepressants, these cases did not report hypertension or possible serotonin syndrome. It is uncertain if the occasional events were possibly associated with the patients unstable psychiatric status following sertraline therapy, or due to potential sertraline-related adverse events. 

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