Venlafaxine approach

A more common approach in difficult to treat cases would be the combination of clomipramine with a SSRI several reports lend support to this practice (Simeon and Thatte, 1990 Figueroa et al., 1998). In this situation, careful attention to the potential pharmacokinetic interactions discussed above are recommended. Sertraline and citalopram are least likely to elevate tricyclic levels due to less potential GYP interactions. By expert consensus, second- (venlafaxine) and third-line (nefazadone and gabapentin) agents may be used when clinical response is inadequate despite a lack of controlled data. Venlafaxine may be substituted for a more typical SSRI while nefazadone or gabapentin may be added to either clomipramine or a SSRI. The combination of venlafaxine with other SSRIs is not generally recommended as it may increase the risk of a serotonin syndrome. The addition of nefazadone to SSRIs presents a lesser risk. 

Nierenberg AA, Amsterdam JD Resistant depression definition and treatment approaches. J Chn Psychiatry 51 (suppl) 39-47, 1990 Nierenberg AA, Adler LA, Peselow E, et al Trazodone for antidepressant-associated insomnia. Am J Psychiatry 151 1069-1072, 1994a Nierenberg AA, Feighner JP, Rudolph R, et al Venlafaxine for treatment-resistant unipolar depression. J Chn Psychopharmacol 14 419-423, 1994b... 

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. 

In contrast to decreased libido seen with SSRIs and venlafaxine, concerns about priapism invariably arise when trazodone is discussed. This adverse effect is rare, occurring in only 1 of 6,000 treated male patients (456, 457). If the patient is informed of this possibility and discontinues the drug promptly, priapism usually resolves without further intervention. Although earlier persistent cases were treated surgically, this approach carries a 50% chance of permanent impotence pharmacological intervention via direct injections into the cavernous bulbosa is preferable ( 458, 459). Using this approach, the chance of permanent impotence is low and depends on the duration of symptoms before treatment (460). This latter fact is another reason to fully inform the male patient on trazodone, so that early detection and intervention can be implemented. 

Level II results showed that patients who failed to benefit from SSRI treatment (citalopram) are good candidates for augmentation (with sustained-release bupropion or with Buspirone) or switching (to sustained-release bupropion or sertraline or sustained-release venlafaxine—three antidepressants with different mechanisms of action). One third of the patients in each group reached remission. Thus, overall, after two well-delivered (robust doses and sufficient duration) medication treatment courses (results for the group who received CBT were not published yet) about 50% of the patients achieved full remission of symptoms. Results from Levels III and IV were not yet available at this time. Once results of all four levels are added up we will have at our disposal an antidepressant roadmap to follow. We will also learn of the percentage of patients who, in spite of these systematic efforts, are still unresponsive to antidepressant treatment and require more drastic or unconventional treatment approaches. 

A delayed response in GAD is not as critical as with acute situational anxiety. A sensible approach (especially in benzodiazepine naive patients) is to start with buspirone for 6-8 weeks, at least 30 mg day increasing over 2-3 weeks to minimise unwanted actions patients should be warned not to expect an immediate benefit. Those who do not respond should receive an antidepressant (SSRI or venlafaxine) for 6-8 weeks at full therapeutic dose. There remain some patients, including those with a... 

Augmentation is called for when there is partial or non-response to the above approaches. Combinations of SSRIs with buspirone, clonazepam, clonidine, inositol, lithium, pindolol, olanzapine, risperidone, trazodone, tryptophan, and venlafaxine have been reported, with limited benefit. To date, only two augmenting agents have been found to be effective in double-blind studies risperidone and pindolol. Augmentation of SSRIs with clomipramine (or vice versa) is a common practice in non-responders however, this combination may lead to a substantial increase in the level of tricyclics in the blood and/or increase the risk of serotonin syndrome. Phenelzine may be helpful in symmetry-related or other atypical obsessions. Electroconvulsive therapy (ECT) should be reserved for severely depressed and suicidal OCD patients. Neurosurgery is the last resort current operations include anterior cingulotomy, anterior capsulotomy, subcaudate tractotomy, and limbic leucotomy. The outcome of such operations is questionable. 

A subsequent study from the Davies group illustrated the synthetic utility of this Rh"-catalyzed intermolecular C—H bond insertion approach by the asymmetric synthesis of antidepressant venlafaxine (Scheme 1.16). ... 

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