Depressive disorders treatment-resistant

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. 

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. 

Schizophrenia is the primary indication for antipsychotic agents. Antipsychotic drugs are also used very extensively in patients with psychotic bipolar disorder (BP1), psychotic depression, and treatment resistant depression. 

Mood symptoms of depression are associated with many conditions in addition to major depressive disorder, including mood and anxiety symptoms in schizophrenia, schizoaffective disorder, bipolar manic/depressed/mixed/rapid cycling states, organic mood disorders, psychotic depression, childhood and adolescent mood disorders, treatment-resistant mood disorders, and many more (see Chapter 10, Fig. 10-6). Atypical antipsychotics are enjoying expanded use for the treatment of symptoms of depression and anxiety in schizophrenia that are troublesome but not severe enough to reach the diagnostic threshold for a major depressive episode or anxiety disorder in these cases the antipsychotics are used not only to reduce such symptoms but hopefully also to reduce suicide rates, which are so high in schizophrenia (Fig. 11 — 53). Atypical antipsychotics may also be useful adjunctive treatments to anti-... 

Favorable tolerability profile leading to off-label uses for many indications other than schizophrenia (e.g., acute bipolar mania bipolar II disorder, including hypomanic, mixed, rapid cycling, and depressed phases treatment-resistant depression anxiety disorders)... 

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

Other agents are also used for the treatment of manic-depressive disorders based on preliminary clinical results (177). The antiepileptic carbamazepine [298-46-4] has been reported in some clinical studies to be therapeutically beneficial in mild-to-moderate manic depression. Carbamazepine treatment is used especially in bipolar patients intolerant to lithium or nonresponders. A majority of Hthium-resistant, rapidly cycling manic-depressive patients were reported in one study to improve on carbamazepine (178). Carbamazepine blocks noradrenaline reuptake and inhibits noradrenaline exocytosis. The main adverse events are those found commonly with antiepileptics, ie, vigilance problems, nystagmus, ataxia, and anemia, in addition to nausea, diarrhea, or constipation. Carbamazepine can be used in combination with lithium. Several clinical studies report that the calcium channel blocker verapamil [52-53-9] registered for angina pectoris and supraventricular arrhythmias, may also be effective in the treatment of acute mania. Its use as a mood stabilizer may be unrelated to its calcium-blocking properties. Verapamil also decreases the activity of several neurotransmitters. Severe manic depression is often treated with antipsychotics or benzodiazepine anxiolytics. 

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 ... 

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]. 

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. 

Thus, although few controlled studies have been performed in well-characterized treatment-resistant populations, further studies using these techniques would prove useful in determining the role of these interventions in the treatment of refractory major depressive disorder. 

Amsterdam JD, Homig-Rohan M Treatment algorithms in treatment-resistant depression. Psychiatr Clin North Am 19 371-386, 1996 Amsterdam JD, Mozley PD Temporal lobe asymmetry with iofetamine (IMP) SPECT imaging in patients with major depression. J Affect Disord 24 43-53, 1992... 

Bher P, Bergeron R, Hebert C Differential effectiveness of pindolol addition in treatment-resistant obsessive-compulsive disorder and depression. Poster No. 7, New Chnical Drug Evaluation Unit (NCDEU) Program, 35th Annual Meeting, Orlando, FL, May 31-June 3, 1995... 

Fava M High-dose fluoxetine in the treatment of depressed patients not responsive to a standard dose of fluoxetine. J Affect Disord 25 229-234, 1992 Fava M, Davidson KG Definition and epiemiology of treatment-resistant depression. 

Psychiatr Chn North Am 19 179-200, 1996 Fava M, Rosenbaum JF, McGrath PJ, et al Dthium and tricyclic augmentation of fluoxetine treatment for resistant major depression a double-blind, controlled study. Am J Psychiatry 151 1372-1374, 1994 Fawcett J Suicide risk factors in depressive disorders and panic disorder. J Clin Psychiatry 53 [suppl 3) 9-13, 1992... 

Nelsen MR, Dunner DL Treatment resistance in unipolar depression and other disorders diagnostic concerns and treatment possibilities. Psychiatr Chn North Am 16 541-566, 1993... 

Before making a definitive diagnosis of a primary depression or concluding the existence of treatment resistance, one must consider the possibility of another concurrent, confounding medical or psychiatric disorder, in addition to depression. 

Post and Kramlinger (386) have also suggested that lithium added to carbamazepine may be useful in treatment-resistant mood-disordered patients. One possible basis for this approach is that carbamazepine, which has a tricyclic ring structure similar to imipramine, may sensitize postsynaptic serotonin receptors in a similar way to standard drugs such as imipramine. A mood stabilizer (e.g., lithium, valproate, carbamazepine) plus antidepressant may benefit some rapid cycling or mixed bipolar patients, attenuating the propensity to switch from mania to depression. 

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