Refractory Depression

Depression refractory to other antidepressants or electroconvulsive therapy PO Initially, 10 mg 3 times/day. May increase to 60 mg/day. 

Other Uses in Geriatric Patient Depression refractory to other measures, anxiety symptoms and related disorders... 

Depression refractory to or intolerant of other therapy PO Initially, lOmgtwiceaday May increase by 10 mg/day at I - to 3-wk intervals up to 60 mg/day in divided doses. 

Nelson JC, Mazure CM Lithium augmentation in psychotic depression refractory to combined drug treatment. Am J Psychiatry 143 363-366, 1986... 

Perhaps the best documented example showing the enhanced efficacy of this serotonin 2A antagonist strategy is the use of the atypical antipsychotics to boost efficacy in nonpsychotic depression refractory to treatment with an SSRI. 

Nyhuis PW, Gastpar M, Scherbaum N. Opiate treatment in depression refractory to antidepressants and electroconvulsive therapy. J Clin Psychopharmacol 2008 28 (5) 593-5. 

Glass lA Antiarrhythmic Agents. Class lA antiarrhythmic agents decrease automaticity, ie, depress pacemaker rates, especially ectopic foci rates produce moderate depression of phase 0 depolarization and thus slow conduction in atria, A-V node, His-Purkinje system, and ventricles prolong repolarization, ie, lengthen action potential duration increase refractoriness and depress excitabiHty. These electrophysiological effects are manifested in the ECG by increases in the PR, QRS, and QT intervals. 

Glass IB Antiarrhythmic Agents. Class IB antiarrhythmic agents produce less inhibition of the inward sodium current than Class lA agents. In normal myocardial tissue, phase 0 may be unaffected or minimally depressed. However, in ischemic or infarcted tissue, phase 0 is depressed. Myocardial tissue exposed to Class IB agents exhibits decreased automaticity, shortened action potential duration, ie, shortened repolarization, and shortened refractory period. Excitability of the myocardium is not affected and conduction velocity is increased or not modified. The refractory period is shortened less than its action potential duration, thus the ratio of refractory period to action potential duration is increased by these agents. The net effect is increased refractoriness. The PR and QT intervals of the ECG are shortened and the QRS interval is unchanged (1,2). 

Pirmenol. Pirmenol hydrochloride, a pyridine methanol derivative, is a racemic mixture. It has Class lA antiarrhythmic activity, ie, depression of fast inward sodium current, phase 0 slowing, and action potential prolongation. The prolongation of refractory period may be a Class III property. This compound has shown efficacy in converting atrial arrhythmias to normal sinus rhythm (34,35). 

Class II drugs are classical (3-adrenoceptor antagonists such as propranolol, atenolol, metoprolol or the short-acting substance esmolol. These drugs reduce sinus rate, exert negative inotropic effects and slow atrioventricular conduction. Automaticity, membrane responsiveness and effective refractory period of Purkinje fibres are also reduced. The typical extracardiac side effects are due to (3-adrenoceptor blockade in other organs and include bronchospasm, hypoglycemia, increase in peripheral vascular resistance, depressions, nausea and impotence. 

Electroconvulsive therapy (ECT) is the application of prescribed electrical impulses to the brain for the treatment of severe depression, mixed states, psychotic depression, and treatment-refractory mania in patients who are at high risk of suicide. It also may be used in pregnant women who cannot take carbamazepine, lithium, or divalproex. 

Fourth, if response is inadequate, consider ECT for treatment-refractory illness and depression with psychosis or catatonia6 Fifth, if response is inadequate, consider adding adjunctive therapies8... 

Mood stabilisers are used to regulate the cyclical change in mood characteristic of bipolar disorder, since they can attenuate both manic and depressive phases. Their main use is as a prophylactic for manic depression and unipolar mania. However, they can also be administered concomitantly with antidepressants for refractory (non-responsive) unipolar depression. 

Hypothyroidism can precipitate a depression and be a risk factor for rapid cycling thyroid supplementation can be used for refractory rapid cycling and augmentation of antidepressants in unipolar depression. 

Lamotrigine is approved for the maintenance treatment of bipolar I disorder. It has been used as monotherapy or add-on therapy for refractory bipolar depression. 

An algorithm for treatment of depression including refractory patients is shown in Fig. 70-1. 

There are a number of interferences that can occur in atomic absorption and other flame spectroscopic methods. Anything that decreases the number of neutral atoms in the flame will decrease the absorption signal. Chemical interference is the most commonly encountered example of depression of the absorption signal. Here, the element of interest reacts with an anion in solution or with a gas in the flame to produce a stable compound in the flame. For example, calcium, in the presence of phosphate, will form the stable pyrophosphate molecule. Refractory elements will combine with 0 or OH radicals in the flame to produce stable monoxides and hydroxides. Fortunately, most of these chemical interferences can be avoided by adding an appropriate reagent or by using a hotter flame. The phosphate interferences, for example, can be eliminated by adding 1 % strontium chloride or lanthanum chloride to the solution. The strontium or lanthanum preferentially combines with the phosphate to prevent its reaction with the calcium. Or, EDTA can be added to complex the calcium and prevent its combination with the phosphate. 

Considerable effort in the field of monoamine reuptake inhibitors is focused on improving antidepressant efficacy since 30-40% of patients do not respond to treatment with currently available agents [6,7], An additional major objective is to enhance the onset of action. Current antidepressants typically require 2-6 weeks of treatment before clinical efficacy is seen [6]. Clinical trials exploring augmentation strategies, in which a DA reuptake inhibitor or a dual NE/DA reuptake inhibitor is combined with an SSRI, have resulted in improved efficacy in depressed patients refractory to SSRI treatment alone [4,5]. The improved results from clinical trials such as these serve to justify the considerable focus on the development of inhibitors that simultaneously block the reuptake of 5-HT, NE and DA. 

Triple reuptake inhibitors (TRIs), which inhibit reuptake at all three transporters, have attracted considerable interest in recent years [77]. The involvement of dopamine reuptake in the etiology of depression and other CNS disorders has been recognized [29,30]. As a result, TRIs have been proposed to offer a faster onset of action and improved efficacy for depression over currently prescribed single or dual action monoamine reuptake inhibitors. Historically, the mesocorticolimbic dopamine pathway is thought to mediate the anhedonia and lack of motivation observed in depressed patients [78,79]. In addition, methylphenidate, both immediate release and extended release formula, has been found to be effective as an augmenting agent in treatment-resistant depression [4]. Furthermore, clinical studies using the combination of bupropion and an SSRI or SNRI have showed improved efficacy for the treatment of MDD in patients refractory to the treatment with SSRIs, SNRIs, or bupropion alone [5,80,81]. 

AS 1990). Several 5-HTlA agonists have been found to produce anxiolytic effects in animal models and in human clinical trials (File et al. 1996 Krummel and Kathol 1987 Goldberg and Finnerty 1979). Furthermore, they have antidepressant effects they augment the antidepressant effects of serotonin reuptake inhibitors, and they decrease the therapeutic latency (Bouwer and Stein 1997 Artigas et al. 1996 Sussman 1998 Rickels et al. 1991 Wieland and Lucki 1990 Jenkins et al. 1990 Fabre 1990). However, results have not been uniformly positive, such as in refractory severe depression (Sussman 1998 Fischer et al. 1998)... 

Opioid A recent study has shown activity of hypericum extracts at opioid receptors (Simmen et al. 1998). Extracts displace naloxone from p and x opioid receptors in the micromolar range (IC50 25 and 90 pg/ml, respectively). In contrast, extracts of the sedative herb Valeriana officinalis do not have this effect. This effect is due to unidentified constituents and not by the flavonoids quercetin or kaemferol. Opioids are known to have effects on emotion, so it is conceivable that activity of hypericum at p and k receptors contributes to its therapeutic effects (Gerra et al. 1998 Tejedor-Real et al. 1995 Walker and Zacny 1998). Although they are not conventional treatment for depression, opioids such as buprenorphine have been effective in treatment of refractory depression (Bodkin et a. 1995). However, for any further conclusions to be drawn, it would be necessary to further e uddate the opioid effects of hypericum to determine what functional effect, if any, hypericum has on the receptors. 

Bodkin JA, Zornberg GL, Lukas SE, Cole JO. (1995). Buprenorphine treatment of refractory depression. J Clin Psychopharmacol. 15(1) 49-57. 

Bouwer C, Stein DJ. (1997). Buspirone is an effective augmenting agent of serotonin selective reuptake inhibitors in severe treatment-refractory depression. Souffi Afr Med J. 87(4 suppi) 534-37, 540. 

Fischer P, Tauscher J, Kufferle B, Kasper S. (1998). Weak antidepressant response after buspirone augmentation of serotonin reuptake inhibitors in refractory severe depression. Int Clin Psychopharmacol. 13(2) 83-86. 

An adequate trial of an antidepressant requires 4-6 weeks of treatment at a recognized therapeutic dose or serum level. If a patient exhibits no response or an nnsatisfactory partial response after an adequate trial, then several options are available. These are discussed in Section 3.2.7 Refractory Depression. 

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