Treatment-resistant depression

Rush and colleagues (217) have published the results of a multicenter trial using VNS for treatment resistant depression. In this group of 67 nonpsychotic, depressed, treatment-resistant patients, a 10-week open trial of VNS produced a 40% to 50% reduction in baseline HDRS, CGI, and Montgomery-Ashberg Depression Rating Scale scores. Further studies are now underway. 

Mood stabilizers or atypical antipsychotics tor bipolar depression, psychotic depression, treatment-resistant depression, or treatment-resistant anxiety disorders... 

Much has been written about "treatment-resistant" depression. Treatment-resistant depression (TRD) refers to a depression that has failed to respond to adequate trials of two or more antidepressants. As many as 30 percent of people with depression may fall into this category—although it probably is closer to 10 to 20 percent. 

Vagus nerve stimulation (VNS) may be used for adult patients with treatment-resistant depression. A pulse generator is surgically implanted under the skin of the left chest, and an electrical lead connects the generator to the left vagus nerve. Stimulation of this nerve sends signals to the brain. This therapy is intended to be used along with traditional therapies, such as pharmacotherapy and ECT.20... 

Fava M. Augmentation and combination strategies in treatment-resistant depression. J Clin Psychiatry 2001 62(suppl 18) 4—11. 

Optimize the dose of mood stabilizing medication(s) before adding on lithium, lamotrigine, or antidepressant (e.g., bupropion or an SSRI) if psychotic features are present, add on an antipsychotic ECT used for severe or treatment-resistant depressive episodes or for psychosis or catatonia... 

Treatment-resistant depression Depression characterized by multiple failed trials of antidepressants and/or electroconvulsive therapy. 

Chen, J., Lu, Z., Jiang, S. D. et al. (2005). Association between polymorphism in the cytochrome P450 enzymes 1A2 2C19 gene and treatment-resistant depression. Shanghai Archive of Psychiatry, 17(2), 95-8. 

Approximately 30-40% of patients will not respond to a given antidepressant and 60-75% may fail to achieve complete remission [16]. Consequently, in its least restricted definition, treatment resistance could be detected in the majority of depressed patients under treatment. Moreover, prior treatment failure negatively influences the response to subsequent antidepressant treatment, decreasing the odds of treatment response by a factor of 15-20% for each failed treatment [17]. The delayed onset of symptom relief (which takes three to eight weeks to occur) and the presence of adverse drug reactions contribute significantly to low treatment compliance. 

Amsterdam JD, Maislin G, Potter L. Fluoxetine efficacy in treatment resistant depression. Prog Neuropsychopharmacol Biol Psychiatry 1994 18 243-261. 

Most treatment-resistant depressed patients have received inadequate therapy. Issues to be considered in patients who have not responded to treatment include the following (1) Is the diagnosis correct (2) Does the patient have a psychotic depression (3) Has the patient received an adequate dose and duration of treatment (4) Do adverse effects preclude adequate dosing (5) Has the patient been compliant with the prescribed regimen (6) Was treatment outcome measured adequately (7) Is there a coexisting or preexisting medical or psychiatric disorder (8) Was a stepwise approach to treatment used (9) Are there other factors that interfere with treatment ... 

Alternatively, the current antidepressant may be augmented (potentiated) by the addition of another agent (e.g., lithium, T3), or an atypical antipsychotic (e.g., risperidone). Risperidone has been shown to be effective in combination with fluvoxamine, paroxetine, or citalopram in treatment-resistant depression. Olanzapine and fluoxetine have been found to be safe and effective in treatment-resistant depression. 

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]. 

Generalized Sociai Anxiety Disorder, Treatment Resistance. A significant minority of patients will not experience a satisfactory treatment response to antidepressant therapy, even after a trial of adequate duration at full strength doses. For those with comorbid depression who are experiencing no benefit from SSRI treatment for either the anxiety or depression, then switching treatment is advisable. The options include switching to another SSRI, a SNRI (venlafaxine or perhaps dulox-etine), or, when other alternatives fail, phenelzine. 

It has been estimated that at least 30% of patients with major depression fail to respond to a 6-week course of a TCA antidepressant. A major problem arises however in the definition of "treatment resistance". To date, there appears to be no internationally acceptable definition of the condition. A practical definition which many clinicians find useful is that treatment resistance occurs when the patient fails to respond to ... 

The MAOIs are as effective as the heterocyclic antidepressants and the newer agents, such as the SSRIs. However, at least two forms of life-threatening toxicity (hepatotoxicity and dietary tyramine-induced hypertensive crisis ) have been associated with their chronic use. For this reason, the MAOIs are not considered first-line agents in the treatment of depression. They are generally reserved for treatment of depressions that resist therapeutic trials of the newer, safer antidepressants. However, a new transdermal formulation of selegiline undergoing clinical trials demonstrates antidepressant efficacy without concerns of liver toxicity or dietary tyramine-induced hypertension. 

Shah, P.J., Ebmeier, K.P., Glabus, M.F., and Goodwin GM (1998) Cortical grey matter reductions associated with treatment-resistant chronic unipolar depression. Controlled magnetic resonance imaging study. Br J Psychiatry 172 527-532. 

Controlled studies involving lipid manipulation in children date back to the 1920s, when the ketogenic diet was pioneered to control treatment-resistant seizures in select pediatric populations (Freeman et al., 1998). However, no controlled evidence is available in children with depression, bipolar disorder, behavioral problems, or ADHD. In the absence of definite empirical data about effectiveness, treatment with EFA supplements should be considered unproven and patients ought to be advised accordingly. 

The initial choice of therapy is also dictated by the severity of the depression (e.g., the severity of depressive symptoms impedes an adequate trial of psychotherapy), subtype of depression (e.g., presence of psychosis, seasonal depression, or treatment-resistant depressions) presence of comorbid disorders, prior treatment history, child and parent motivation toward treatment, and the clinician s motivation and expertise in implementing any specific intervention. 

Case reports have suggested that adding stimulant medications or combining a SSRI and a TCA or bupropion may also be effective (APA, 2000), but these combinations need to be done with caution, given the possibility of drug interactions (e.g., SSRIs cytochrome inhibition leading to toxic TCA levels). Additionally, in adults, the combination of antidepressants and psychotherapy (CBT, IPT) for patients with severe or treatment-resistant depression has been found useful (APA, 2000 Keller et al., 2000). 

Some randomized control trials have shown that TMS is efficacious and safe for the treatment of adults with MDD (with and without treatment-resistant depressions) (e.g., Grunhaus et ah, 2000 Martis and Jan-icak, 2000). However, the use of TMS has not been standardized and there is controversy regarding the methodology used in some studies. 

Poirier, M.F. and Boyer, P. (1999) Venlafaxine and paroxetine in treatment-resistant depression double-blind, randomized comparison. Br J Psychiatry 175 12-16. 

Birmaher, B., Waterman, G.S., Ryan, N.D., Perel, J., McNabb, J., Balach, L., Beaudry, M.B., Nasr, F.N., Karambelkar, J., Elterich, G., Quintana, H., Williamson, D.E., and Rao, U. (1998) Randomized, controlled trial of amitriptyline versus placebo for adolescents with treatment-resistant major depression. J Am Acad Child Adolesc Psychiatry 37 527-535. 

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