Older Antidepressants

The tricyclics, such as clomipramine (Anafranil), amitriptyline (Elavil), and imipramine (Tofranil), have been used for several decades. I have previously described their central nervous system toxic effects in some detail (Breggin, 1983b see also Breggin, 1991b). This section will therefore be abbreviated. A list of some of the older antidepressants can be found in the appendix. 

Most of the older antidepressants are called tricyclic because their chemical nucleus has the basic tricyclic structure of the original pheno-thiazine neuroleptic, chlorpromazine, or Thorazine (Bassuk et ah, 1977 Pauker, 1981). Of extreme importance, the antidepressant amoxapine (Asendin) is turned into a neuroleptic in the body, producing the same problems as any other neuroleptic, including tardive dyskinesia (chapters 3 and 4). 

Bassuk and Schoonover (1977) noted that tricyclic antidepressants can cause a toxic syndrome similar to the neuroleptics  

In my clinical practice, I have occasionally seen otherwise normal patients who were put into states of apathy or lethargy by very small doses of tricyclic antidepressants (e.g., 10 mg to 25 mg of amitriptyline) given to them for nonpsychiatric purposes, especially to treat headache or diarrhea. Depressed patients are frequendy made more depressed by these drugs without the spellbound patients or their doctors perceiving that the drug is causing the worsened condition. 

As already described, the FDA now requires a broad range of warnings on antidepressant labels. There should no longer be any scientific doubt about the range and frequency of abnormal reactions in children 

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The continuing development of antidepressant agents has increased the availability of newer dmgs that have similar efficacy but are more expensive than the older antidepressants (Song et al, 1993). This chapter addresses the complex question of whether there is clear evidence that the use of any single antidepressant or group of antidepressants is more cost-effective than any other. 

T3 is the best studied of these and is a reasonable alternative, but many prefer adding a second antidepressant in order to recapture some of the rich pharmacology of the older antidepressants. Stimulants are highly recommended for medically compromised patients who need a rapid response, and buspirone is probably best... 

Spina, E. and Pemcca, E. (1994) Newer and older antidepressants a comparative review of drug interactions. CNS Drugs, 2, 479-497. 

Trazodone is an older antidepressant that is associated with significant sedation. Currently, trazodone is not recommended as a first-line antidepressant because of an increased risk of orthostatic hypotension, arrhythmias, and priapism. Also, compared with other available antidepressants, trazodone does not offer an advantage in terms of therapeutic efficacy. However, trazodone may be useful in patients with insomnia. It is currently common practice to use low doses of trazodone (e.g., 50-100 mg) to assist with initial insomnia while starting treatment with one of the newer antidepressants to address the underlying depression. If this strategy is used, we recommend tapering the trazodone dose and discontinuing treatment with trazodone after 4—6 weeks. 

The most common side effects of the older antidepressants, especially those of the sedative type, are vegetative and mostly due to the anticholinergic action of these products dry mouth, difficulties of visual accommodation, constipation, impotence in men, dizziness, increased sweating and palpitations. Of medical... 

Another approach to correct neurotransmission is to inhibit the reuptake of the neurotransmitters into their presvnaptic endings. If the presynaptic reuptake mechanism of a neurotransmitter is blocked then more of the neurotransmitter will stay in the synaptic cleft and be functionally available. Many antidepressant drugs, called reuptake inhibitors , are thought to act via this mechanism. If selective for serotonin they are called selective serotonin reuptake inhibitors (SSRIs, Chapter 1), but if selective for both serotonin and noradrenaline they are called serotonin noradrenaline reuptake inhibitors (SNRIs). Most older antidepressants, such as the tricyclic compounds amitriptyline, imipramine and clomipramine, have little specificity for any of the neurotransmitters fluoxetine, paroxetine, citalopram and a few others are specific for serotonin venlafaxine is a representative of the SNRIs. A more recent mixed-uptake inhibitor is mirtazepine, and some similar compounds are about to be launched. 

Mastering this information can be facilitated by understanding antidepressants from the perspective of their clinical pharmacology (i.e., their mechanisms of action). This is made easier by understanding how newer antidepressants were developed using the older antidepressants as a blueprint about what mechanisms could mediate an antidepressant response and what mechanisms only mediated adverse effects. Thus, it is important to understand the concept of rational drug development in psychiatry. 

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). 

Rudorfer MV, Manji HK, Potter WZ Comparative tolerability profiles of the newer versus older antidepressants. Drug Saf 1994 10(1) 18. [PMID 8136085]... 

Monoamine oxidase inhibitors (eg, tranylcypromine, phenelzine) are older antidepressants that are occasionally used for resistant depression. They can cause severe hypertensive reactions when interacting foods or drugs are taken (see Chapters 9 and 30), and they can interact with the selective serotonin reuptake inhibitors (SSRIs). 

The FDA published its final version of the class label for all antidepressants on January 26, 2005. The FDA applied the new label changes to all 34 antidepressants on the market, including older, more sedating antidepressants such as amoxapine (Asendin), trazodone (Desyrel), amitriptyline (Elavil), doxepin (Sinequan), and imipramine (Tofranil). The last-minute inclusion of the older antidepressant was an act of deference to the manufacturers of the newer antidepressants, in effect tarring all antidepressants with a brush meant only for the newer ones. 

Damluji and Ferguson (1988) reviewed paradoxical worsening of depressive symptomatology caused by antidepressants in an article of the same title and reported four cases of their own caused by the older antidepressants amoxapine, desipramine, nortriptyline, and trazodone. The APA National Task Force on Women and Depression (1990) report on benzodiazepines also cited the problem of depression and suicide from tricyclic antidepressants. 

Tragically, while the older antidepressant drugs cannot prevent suicide and can cause it, in relatively small amounts, they can become lethal instruments in the hands of suicidal patients. As little as 1 week s supply of most tricyclics can cause death, often due to cardiac dysfunction. In combination with other drugs, their lethality increases. Thus millions of depressed, suicidal patients are given the tool with which to kill themselves. By 1981, the tricyclics were overtaking the barbiturates as the medications most frequently involved in serious overdoses ( Tricyclics, 1981). The tricyclics remain a major public health problem as agents of suicide (Henry et al., 1995). 

As noted earlier in the chapter, although several thousand patients were involved in studies of various kinds, I counted only 286 who actually finished the three placebo-controlled protocols (groups of studies) used for approval. Many patients dropped out because of adverse stimulant reactions. Prozac seldom proved any better than placebo and was not as good as the older antidepressants. It was so stimulating that sedatives were often given along with it. 

Spurred on by Laughren s (1991) critique, an exchange of memos occurred between Paul Leber and his boss, Robert Temple, Director, Office of Drug Evaluation 1. The continuing subject was the approval of Zoloft, whose efficacy as an antidepressant remained in doubt up to the last minute. Temple noted that Zoloft was not being approved in some European countries because of its lack of robustness in the efficacy trials. Zoloft often failed to do any better than placebo in studies in the United States and never did as well as the older antidepressant amitriptyline. Despite these pervasive failures, one positive study and two supportive studies were found sufficient to earn approval. 

In my clinical practice, I have seen relatively few cases of very severe, lasting withdrawal reactions from the older antidepressants in comparison to the newer ones, with which serious withdrawal problems are frequent. 

All the older antidepressants can cause psychiatric adverse drug reactions, including mania and psychosis, but they much less commonly come up in my clinical and medical-legal experience. A more complete list can be found in various textbooks, especially Drug Facts and Comparisons (2007), a readily available annual publication. 

When SSRIs were developed, we incorporated them into our ethnopsychopharmacological research. Initially, we compared patterns of use of the newer antidepressants with those of the older ones (TCAs). By the mid 1990s, it was becoming clear that SSRIs were rapidly replacing TCAs and other older antidepressant agents as drugs of first choice in the treatment of depression. 

Contents Introduction, history and brain basics—Older antidepressants tricyclics and monoamine oxidase inhibitors—Selective serotonin reuptake inhibitors—Second generation antidepressants—Lithium, a medication for bipolar depression—Natural depressants—Teens and antidepressants trends and attitudes—Case study one girl s experience with antidepressants. 

Older Antidepressants Tricyclics and Monoamine Oxidase Inhibitors... 

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