Antidepressants long-term effects

Psychotherapy looks even better when its long-term effectiveness is assessed.17 Formerly depressed patients are far more likely to relapse and become depressed again after treatment with antidepressants than they are after psychotherapy. As a result, psychotherapy is significantly more effective than medication when measured some time after treatment has ended, and the more time that has passed since the end of treatment, the larger the difference between drugs and psychotherapy. This long-term advantage of psychotherapy over medication is independent of the severity of the depression. Psychotherapy outperforms antidepressants for severely depressed patients as much as it does for those who are mildly or moderately depressed.18... 

Currently, many physicians adopt a benzodiazepine-sparing strategy by using benzodiazepines when necessary but conservatively. That is, benzodiazepines can often be helpful when treatment is initiated or when a rapid-onset therapeutic effect is desired. They can also help improve the short-term tolerability of SSRIs by blocking the jitteriness and exacerbation of panic sometimes observed when initiating treatment with an SSRI or other antidepressant. Benzodiazepines can also be useful to top up the patient s treatment on an as-needed basis for sudden and unexpected decompensation or short-term psychosocial stressors. Finally, if a patient is not fully responsive to an antidepressant or combinations of antidepressants, long-term treatment with concomitant benzodiazepines and antidepressants may become necessary to effect full or adequate control of symptoms. Sometimes, once symptoms are suppressed for several months to a year, the benzodiazepine can be slowly discontinued and the patient maintained long-term on the antidepressant alone. The consequences of inadequate treatment of panic disorder can be very severe loss of social and oc-... 

The selective serotonin-reuptake inhibitors (SSRI) are a new group of chemically unique antidepressant drugs that specifically inhibit serotonin reuptake (see Figure 12.3). This contrasts with the tricyclic antidepressants that nonselectively inhibit the uptake of norepinephrine, and serotonin, and block muscarinic, H histaminic and a -adrenergic receptors. Compared with tricyclic antidepressants, the SSRIs cause fewer anticholinergic effects and lower cardiotoxicity. However, the newer serotonin reuptake inhibitors should be used cautiously until their long-term effects have been evaluated. 

Potential behavioral teratogenicity—the long-term effect of the medication on the functioning and behavior of the child many years later is an unknown factor for most medications used today, but no harm in this area is known for the antidepressants commonly prescribed. 

The British medical journal, Lancet, recently published a meta-analysis (systemic review of research articles) that looked at the long-term effects of severely depressed patients taking the SSRI Zoloft (sertraline). Most patients not only felt much better after short-term antidepressant therapy but were able to function better, a surprising result considering the seriousness of the illness. A majority of those polled were much improved in just six to twelve weeks however, they tended to lose their psychosocial gains after discontinuing their medication. Overall, 70 percent of patients who discontinued SSRIs relapsed, compared to 40 percent of those who... 

In any case, there is a pressing need for a systematic study of adolescent depression, comparing psychotherapy or cognitive behavioral thereapy (CBT) and antidepressants, or the combination of both treatments. The National Institute of Mental Health (NIMH) has organized a multicenter study which will analyze the long-term effectiveness of Prozac versus CBT. Results of the study, called Treatment for Adolescent Depression Study (TADS), will not be published for several years, but it is hoped that the results will help resolve whether antidepressants in teens are beneficial and safe. 

There are two issues of concern which are associated with irreversible MAOIs involving the display of liver toxicity, particularly with hydrazines, and the permanent inactivation of both MAO-A and -B isoforms. The replacement of MAOs requires protein synthesis which may take up to 14 days. From the antidepressant viewpoint, only a selective blockage of serotonin metabolism may be of interest in order to increase serotonin availability. However, this long-term effect significantly reduces metabolism of a variety of other biogenic amines, which leads to their accumulation, which is not necessarily desired. This leads to an excessive availability of tyramine and others, which ultimately leads to increased release of noradrenaline that may result in the stimulation of cardiovascular sympathetic nervous system activity. As a consequence, potentially fatal hypertensive crises and cerebral haemorrhage can occur (Fig. 18.22). This phenomenon has often been termed the cheese effect, in order to reflect the fact that tyramine is present in a variety of foods such as wine, cheese and other fermented food and drink products. It would appear, however, that under carefully controlled and restricted dietary conditions such a risk can be minimised. 

Antidepressants are commonly used to treat both acute withdrawal and persistent anxiety or insomnia. There is evidence to suggest that they are effective in relieving some acute abstinence symptoms, but it has been more difficult to establish their effectiveness in long-term discontinuation. Antidepressants with sedative and antianxiety effects are the preferred drugs. 

The pharmacoeconomics of the anxiety disorders has received litde attention. In the past drug costs were largely incurred by use of benzodiazepines, most of which are available in generic forms and are cheap. They are effective and acceptable in the short term. Long-term use is associated with the risk of physical dependence, with an adverse risk—benefit ratio and high cost terms to facilitate withdrawal. There is now a trend towards the use of antidepressants in the anxiety disorders. Clinical experience has been followed by formal trial evaluation. 

Tricyclic antidepressants are not licensed for use in the anxiety disorders, so in theory the SSRIs should not be compared with them in cost-effectiveness terms. The SSRIs and venlafaxine are supplanting benzodiazepines as the latter s long-term problems become more appreciated. The SSRIs will take an increasing proportion of the market. However, in comparison with the overall costs of the anxiety disorders, this drug expenditure can be justified. Further cost-offset and cost-effectiveness studies will help hammer this point home. 

Benzodiazepines are used commonly in SAD however, there are limited data supporting their use. Clonazepam has been effective for social anxiety, fear, and phobic avoidance, and it reduced social and work disability during acute treatment.58 Long-term treatment is not desirable for many SAD patients owing to the risk of withdrawal and difficulty with discontinuation, cognitive side effects, and lack of effect on depressive symptoms. Benzodiazepines may be useful for acute relief of physiologic symptoms of anxiety when used concomitantly with antidepressants or psychotherapy. Benzodiazepines are contraindicated in SAD patients with alcohol or substance abuse or history of such. 

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... 

Virtually all types of drug that have been shown to be effective in major depression exert profound effects on the functioning of the serotoninergic or noradrenergic systems, or both. Although some treatments have been shown to decrease the sensitivity of certain postsynaptic 5-HT and NE receptors, it is generally believed that it is an enhancement of neurotransmission in these systems that is responsible for the improvement of the core symptoms of depression. For instance, long-term administration of tricyclic antidepressants (TCAs) or monoamine oxidase inhibitors (MAOIs) decreases the density of (3-adrenoceptors and cortical 5-HT2 receptors (Blier and Abbott 2003). 

---