Tricyclic antidepressants, combined

Expensive, non-narcotic, "narcotic -tricyclic antidepressant combination analgesic potential use in chronic pain demonstrated efficacy in a variety of pain syndromes minimal cardiovascular and respiratory side effects... 

Heiman EM. Cardiac toxicity with thioridazine-tricyclic antidepressant combination. J Nerv Ment Dis 1977 165(2) 139-43. 

Ciraulo DA, Jaffe JH Tricyclic antidepressants in the treatment of depression associated with alcoholism. Clin Psychopharmacol 1 146—150, 1981 Ciraulo DA, Nace E Benzodiazepine treatment of anxiety or insomnia in substance abuse patients. Am J Addict 9 276—284, 2000 Ciraulo DA, Barnhill JG, Jaffe JH, et al Intravenous pharmacokinetics of 2-hydroxy-imipramine in alcoholics and normal controls. J StudAlcohol 51 366-372, 1990 Ciraulo DA, Knapp CM, LoCastro J, et al A benzodiazepine mood effect scale reliability and validity determined for alcohol-dependent subjects and adults with a parental history of alcoholism. Am J Drug Alcohol Abuse 27 339—347, 2001 Collins MA Tetrahydropapaveroline in Parkinson s disease and alcoholism a look back in honor of Merton Sandler. Neurotoxicology 25 117-120, 2004 COMBINE Study Research Group Testing combined pharmacotherapies and behavioral interventions in alcohol dependence rationale and methods. Alcohol Clin Exp Res 27 1107-1122, 2003a... 

Guidelines agree that when antidepressants must be used, they should be combined with a mood-stabilizing drug to reduce the risk of mood switch to hypomania or mania.17,41 The question of which antidepressant drugs are less likely to cause a mood switch is not resolved. Anecdotal reports suggested bupropion may be less likely to cause this effect, but systematic reviews have not supported this conclusion. Prevailing evidence recommends that tricyclic antidepressants be avoided.41,43... 

Compared to antipsychotics, there are even fewer studies on the prescribing patterns of antidepressants done in Asian countries. Pi etal. (1985) conducted a survey of psychotropic prescribing practices reported by psychiatrists in 29 medical schools in 9 Asian countries. Daily dose range of tricyclic antidepressants (TCAs) such as amitriptyline, imipramine, and nortriptyline in Asian countries was comparable to the practice in USA. This is despite differences found between Asian and non-Asian populations in the pharmacokinetics of TCAs (Pi et al, 1993). A questionnaire on the practical prescribing approaches in mood disorders administered to 298 Japanese psychiatrists was reported by Oshima et al. (1999). As first-line treatment, the majority of respondents chose newer TCAs or non-TCAs for moderate depression and older TCAs for severe depression. Combination of antidepressants and anxiolytics was preferred in moderate depression, while an antidepressant and antipsychotic combination was common in severe psychotic depression. Surprisingly, sulpiride was the most favored drug for dysthymia. In a naturalistic, prospective follow-up of 95 patients with major depression in Japan, the proportion of patients receiving 125 mg/day or less of imipramine was 69% at one month and 67% at six months (Furukawa et al., 2000). 

Many neurotransmitters are inactivated by a combination of enzymic and non-enzymic methods. The monoamines - dopamine, noradrenaline and serotonin (5-HT) - are actively transported back from the synaptic cleft into the cytoplasm of the presynaptic neuron. This process utilises specialised proteins called transporters, or carriers. The monoamine binds to the transporter and is then carried across the plasma membrane it is thus transported back into the cellular cytoplasm. A number of psychotropic drugs selectively or non-selectively inhibit this reuptake process. They compete with the monoamines for the available binding sites on the transporter, so slowing the removal of the neurotransmitter from the synaptic cleft. The overall result is prolonged stimulation of the receptor. The tricyclic antidepressant imipramine inhibits the transport of both noradrenaline and 5-HT. While the selective noradrenaline reuptake inhibitor reboxetine and the selective serotonin reuptake inhibitor fluoxetine block the noradrenaline transporter (NAT) and serotonin transporter (SERT), respectively. Cocaine non-selectively blocks both the NAT and dopamine transporter (DAT) whereas the smoking cessation facilitator and antidepressant bupropion is a more selective DAT inhibitor. 

Agents Acetaminophen or NSAID combinations with opioids Adjuncts Tricyclic antidepressants Anticonvulsants Radiopharmaceuticals (Bone pain) Acetamnophen (See above) Opioids Titrate Amitriptyline 10-50 mg Imipramine 10-50 mg NSAIDs (See above) Gabapentin (Neurontin) 3.6 g... 

Changing a patient from one MAOI to another, or to a TCA, requires a "wash-out" period of at least 2 weeks to avoid the possibility of a drug interaction. There is evidence to suggest that a combination of an MAOI with clomipramine is more likely to produce serious adverse effects than occurs with other TCAs. Regarding the newer non-tricyclic antidepressants, it is recommended that a "wash-out" period of at least 5 weeks be given before a patient on fluoxetine is given an MAOI this is due to the very long half-life of the main fluoxetine metabolite norfluoxetine. 

MAOIs should not be administered together with or immediately following tricyclic antidepressants (TCAs). At least 14 days should elapse between the discontinuation of the MAOIs and the institution of a TCA. Some TCAs have been used safely and successfully in combination with MAOIs. 

Dmg-induced serotonin syndrome is generally mild and resolves when the offending drugs are stopped. However, it can be severe and deaths have occurred. A large number of drugs have been implicated including tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs), selective serotonin re-uptake inhibitors (SSRIs), pethidine, lithium, and dextromethorphan. The most severe type of reaction has occurred with the combination of selective serotonin re-uptake inhibitors and monoamine oxidase inhibitors. Both non-selective MAOIs such as phenelzine and selective MAOIs such as moclobemide and selegiline have been implicated. 

A considerable number of tricyclic antidepressants have been developed in the past, although with slight differences in their pharmacological activities, ah with similar efficacy. They are primarily indicated for the treatment of endogenous depression. However this does not exclude efficacy in patients in whom the depression is associated with organic disease or in patients with reactive depression or depression combined with anxiety. They may also benefit patients during the depressive phase of manic-depressive disorder. For some also efficacy has been claimed in panic states, phobic disorders, and in obsessive-compulsive disorders. 

Tricyclic antidepressants are notorious for their risk to be involved in drug-drug interactions. Additive anticholinergic effects can be expected in combination with antihistamines, antipsychotics and anticholinergic-type anti-Parkinson agents. Hepatic enzyme-inducing agents increase their hepatic metabolism while enzyme inhibitors may potentiate the effects of tricyclics. Concomitant use with monoamine oxidase inhibitors will produce hypertension, hyperpyrexia and convulsions. 

Some selective serotonin re-uptake inhibitors are powerful inhibitors of cytochrome P450 enzymes and the metabolism of e.g. tricyclic antidepressants can be inhibited resulting in serious toxicity. Additive sedation can be expected when given in combination with CNS depressants such as benzodiazepines but also with alcohol. Selective serotonin re-uptake inhibitors should not be used in combination with monoamine oxidase inhibitors as fatal reactions have been reported. 

The prevalence of concurrent prescriptions raises concern regarding drug interactions with stimulants. Stimulants, especially MPH, have been used to augment the effects of tricyclic antidepressants in the treatment of refractory depression. Although one early report claimed that circulating levels of imipramine can rise seven fold when taken concurrently with MPH (Wharton et al., 1971), a more recent study found that combining stimulants with desipramine (DMI) did not increase the plasma level of DMI relative to children treated with DMI alone (Cohen et al., 1999). 

Coadministration of beta-blockers can potentiate rebound hypertension upon discontinuation of medications, and it is therefore recommended that the beta-blocker be withdrawn before the tt2 agonist (Physicians Desk Reference, 2001). Tricyclic antidepressants may also produce changes in sinus node and AV conduction, and it is recommended that they be used cautiously in combination with tt2 agonists (Physicians Desk Reference, 2001). However, in child psychiatric practice, there has been debate about whether there are adverse interactions related to concomitant use of tricyclics and tt2 agonists. Finally, the tt2 agonists may potentiate the effects of CNS depressants (e.g., barbiturates) or other medications that produce sedation, so lower doses of each may be warranted. 

Medications with serotonergic activity may also have other monaminergic or sympathomimetic activity. Combining MAOIs with these medications may result in a complex side effect profile. For example, combining meperidine or dextromethorphan with MAOIs may result in respiratory depression, in addition to symptoms of serotonin excess. Furthermore, interactions between MAOIs and tricyclic antidepressants (TCAs) more commonly result in potentiating shared adverse events such as othostatic hypotension, as opposed to hyperadrenergic crises or the serotonin syndrome. 

Amsterdam JD Use of high dose tranylcypromine in resistant depression, in Refractory Depression. Edited by Amsterdam JD. NewYork, Raven, 1991,pp 123-130 Amsterdam JD, Berwish N Treatment of refractory depression with combination re-serpine and tricyclic antidepressant therapy. J Clin Psychopharmacol 7 238-242, 1987... 

Some patients with bipolar disorder will need antidepressants. Although the switch rate into mania or induction of rapid cychng by antidepressants is controversial, these agents do appear to present a risk for some patients, often with devastating consequences. Therefore, when a patient with bipolar disorder is prescribed an antidepressant, it should only be in combination with a medication that has established antimanic properties. Controlled comparative data on the use of specific antidepressant drugs in the treatment of bipolar depression are sparse. Current treatment guidelines extrapolate from these few studies and rely heavily on anecdotal chnical experience. Overah, tricyclic antidepressants should be avoided when other viable treatment options exist. Electroconvulsive therapy should be considered in severe cases. 

Viewed as a whole, this investigation supports the view that tricyclic antidepressants are particularly effective in cases of endogenous depression, whereas psychotherapy, possibly in conjunction with drug therapy, constitutes the best solution in cases of situative depression (which would probably be termed reactive depression in the terminology used hitherto). It is interesting to note that the combination of drug therapy with psychotherapy provided additional benefit in patients with endogenous depression. It must, however, be stated that this final conclusion is only based on a fairly small subsample. 

Preskorn SH, Beber JH, Paul JC, et al. Serious adverse effects of combining fluoxetine and tricyclic antidepressants. Am J Psychiatry 1990 147 532. 

Treatment Implications. A review of response rates found that only 35% of patients with psychotic depression responded to treatment with a tricyclic antidepressant alone versus 67% of patients with nonpsychotic depression (Table 6-6) (13). Yet these patients have a better response to electroconvulsive therapy (ECT) (14). These patients have also been found to respond to combined treatment with an antidepresssant and an antipsychotic in comparison with either an antidepressant or antipsychotic alone (15). Despite these data, one study found that less than 50% of patients with psychotic depression referred to an ECT service had been treated with an antipsychotic and only 15% had received a daily dose equivalent to 200 mg or more or chlorpromazine ( 16). 

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