Venlafaxine antidepressant effects

Serotonin-Boosting Antidepressants. The SSRIs have also been studied in the treatment of generalized social anxiety disorder, and paroxetine, sertraline, and venlafaxine are effective. Preliminary data suggests that the serotonin-boosting atypical antidepressants (mirtazapine and nefazodone) may also be helpful. Like the MAOIs, they appear to be effective at doses comparable to those used to treat depression. They may help avoidant patients to gradually increase their social interaction and become more assertive. 

In contrast to the SSRIs, venlafaxine has an ascending dose-response curve consistent with its sequential, concentration (and hence dose) dependent effects on serotonin and NE uptake pumps (Table 7-9). At 225 mg per day, the magnitude of the antidepressant effect is 50% higher than that seen with the SSRIs. Also consistent with its dual mechanism of action at higher concentrations, venlafaxine at a dose of 225 mg per day produced an antidepressant response in hospitalized patients with melancholia superior to both placebo and fluoxetine (114, US, 116, H7, H8, H9, 120, 121, 122, 123, 124,125, 126,127, 128,129, 130,131, 132,... 

Nefazodone has some unusual pharmacological properties, not only inhibiting serotonin uptake, but also blocking the 5-HT 2a receptor. It may be that the antidepressant effect of serotonin agents is due to mediation of 5-HT transmission in the absence (or even the blockade) of 5-HT2a transmission. As a result of these actions, nefazodone is even more specific in terms of affecting a subtype of serotonin receptor than are the SSRIs or venlafaxine. 

Optimal dosing with venlafaxine differs from that of both TCAs and SSRIs. Venlafaxine is like the SSRIs and different from the TCAs in that a therapeutic dose (i.e., 75 mg per day) can be started from the beginning. Unlike the SSRIs, however, dose escalation with venlafaxine does increase the magnitude of the antidepressant effect, which supports increasing the dose in the event of an inadequate response to the initial trial ( Table 7-9). Venlafaxine in its sustained release formulation can be given once a day, just like the SSRIs and TCAs. 

The serotonin syndrome is thought to occur because venlafaxine can inhibit serotonin re-uptake (its antidepressant effect is related to this aetivi-ty), and MAOIs and RIMAs inhibit the metabolism of serotonin. The result is an increase in the concentrations of serotonin apparently causing overstimulation of the 5-HTjj, receptors in the brain and spinal cord. See also the serotonin syndrome , (p.9). 

Venlafaxine (48) is a stmcturaHy novel phenylethylamine derivative that strongly inhibits both noradrenaline and serotonin reuptake. It lacks anticholinergic, antihistaminergic, and antiadrenergic side effects. As compared to placebo, most common adverse events are nausea, somnolence, dizziness, dry mouth, and sweating. Venlafaxine-treated patients also experienced more headaches and nausea, but less dry mouth, dizziness, and tremor than patients treated with comparator antidepressants. 

Antidepressants are used in the treatment of neuropathic pain and headache. They include the classic tricyclic compounds and are divided into nonselective nor-adrenaline/5-HT reuptake inhibitors (e.g., amitriptyline, imipramine, clomipramine, venlafaxine), preferential noradrenaline reuptake inhibitors (e.g., desipramine, nortriptyline) and selective 5-HT reuptake inhibitors (e.g., citalopram, paroxetine, fluoxetine). The reuptake block leads to a stimulation of endogenous monoaminer-gic pain inhibition in the spinal cord and brain. In addition, tricyclics have NMDA receptor antagonist, endogenous opioid enhancing, Na+ channel blocking, and K+ channel opening effects which can suppress peripheral and central sensitization. Block of cardiac ion channels by tricyclics can lead to life-threatening arrhythmias. The selective 5-HT transporter inhibitors have a different side effect profile and are safer in cases of overdose [3]. 

Antidepressants Desipramine, imipramine, sertraline, fluoxetine, paroxetine, venlafaxine, bupropion, nefazodone, mirtazapine, gepirone, amineptine Mixed findings suggest that better designed studies may find a niche for some of these drugs. Amineptine was effective for withdrawal symptoms. 

Tricyclic antidepressants are not licensed for use in the anxiety disorders, so in theory the SSRIs should not be compared with them in cost-effectiveness terms. The SSRIs and venlafaxine are supplanting benzodiazepines as the latter s long-term problems become more appreciated. The SSRIs will take an increasing proportion of the market. However, in comparison with the overall costs of the anxiety disorders, this drug expenditure can be justified. Further cost-offset and cost-effectiveness studies will help hammer this point home. 

A number of non-hormonal therapies have been studied for symptomatic management of vasomotor symptoms, including antidepressants [e.g., selective serotonin reuptake inhibitors (SSRIs) and venlafaxine], herbal products (e.g., soy, black cohosh, and dong quai), and a group of miscellaneous agents (e.g., gabapentin, clonidine, and megestrol). The choice of therapy depends on the patient s concomitant disease states, such as depression and hypertension, and the risk for potential adverse effects. 

SSRIs are theorized to reduce the frequency of hot flashes by increasing serotonin in the central nervous system and by decreasing LH. Of the SSRIs, citalopram, paroxetine, and sertraline all have been studied and have demonstrated a reduction in hot flashes while treating other symptomatic complaints such as depression and anxiety.33 Venlafaxine, which blocks the reuptake of serotonin and norepinephrine, has demonstrated a reduction in hot flashes primarily in the oncology population.34 Overall, these antidepressant medications offer a reasonable option for women who are unwilling or cannot take hormonal therapies, particularly those who suffer from depression or anxiety. These agents should be prescribed at the lowest effective dose to treat symptoms and may be titrated based on individual response. 

Although many patients believe that dietary supplements will not interact with medications, recent literature suggests otherwise. Recently, many St. John s wort-drug interactions have been reported in the literature. Cases of patients developing symptoms of serotonin syndrome have been reported with St. John s wort alone and in concomitant therapy with other antidepressants such as monoamine oxidase inhibitors, serotonin reuptake inhibitors, and venlafaxine. St. John s wort may exacerbate the sedative effects of benzodiazepines, alcohol, narcotics, and other sedatives. St. John s wort may decrease the levels of protease inhibitors, cyclosporine, digoxin, and theophylline. 

These types of antidepressant were introduced around 10 years after the SSRIs. They include the serotonin noradrenaline reuptake inhibitor venlafaxine and the selective noradrenaline reuptake inhibitor reboxetine. Although there are fewer data about these drugs, clinical experience has shown they are well tolerated and, unlike the SSRIs, they are only weak inhibitors of drug metabolism (Kent, 2000). Depression is a common psychiatric disorder seen in the elderly and often remains untreated or inadequately treated (Forsell and Fastbom, 2000). Venlafaxine was shown to improve the mood in a group of 36 older patients without any effect on cognitive function, an important consideration where there is the possibility of the coexistence of mild or undiagnosed dementia (Tsolaki et al., 2000). 

Tsolaki M, Fountoulakis KN, Nakopoulou E and Kazis A (2000). The effect of antidepressant pharmacotherapy with venlafaxine in geriatric depression. International Journal of Geriatric Psychopharmacology, 2, 83-85. 

The most effective treatment for cataplexy is the tricyclic antidepressants, fluoxetine, or venlafaxine. Imipramine, protriptyline, clomipramine, fluoxetine, and nortriptyline are effective in about 80% of patients. 

Tricyclic drugs have, as the name implies, a three-ring structure, and interfere with reuptake of norepinephrine and/or serotonin into axon terminals. Tricyclic drugs include imipramine (Tofranil), amitriptyline (Elavil), clomipramine (Anafranil), and nortriptyline (Pamelor, Aventil). Tricyclics have the occasional but unfortunate cardiovascular side effects of arrhythmia and postural hypotension. Newer, nontricyclic antidepressants have been developed that are collectively referred to as SSRIs. These have a potent and selective action on serotonin, and lack the cardiovascular side effects of the tricyclics. These include fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), and fluvoxamine (Luvox). A fifth SSRI, citalopram (Celexa) has been used in Europe and has recently been approved in the United States. Venlafaxine (Effexor) blocks reuptake of norepinephrine and serotonin, while bupropion (Wellbutrin) acts on both dopamine and norepinephrine. 

In addition to acute effects, chronic use of antidepressants causes chronic receptor adaptations. For example, venlafaxine blocks reuptake... 

The traditional scheme is complicated by the fact that some antidepressants exhibit characteristics of more than one class. For example, clomipramine, a tricyclic antidepressant (TCA) with side effects and toxicity similar to other TCAs, works more like the selective serotonin reuptake inhibitors (SSRls). Similarly, venlafaxine and duloxetine, which are usually grouped with the atypical antidepressants, have a side effect and safety profile comparable to the SSRls. Although a classihcation system based on mechanism of action offers some advantage (see Table 3.7), even this scheme is limited by the fact that antidepressants that work in the same way may have widely divergent side effect and safety profiles. In the following discussion, the traditional classification system is adopted. Although fraught with problems and inconsistencies. 

When starting a SSRI, the abrupt increase in serotonin may cause side effects. In the brain, the short-term effects include headache, sleep disturbance, nervousness, anxiety, and tremulousness. The digestive system effects include nausea, loose stools, decreased appetite, and indigestion. Most of these effects are mild and shortlived or can be managed with over-the-counter remedies. Nausea, for example, can be minimized by taking a SSRI after meals. These effects are also commonly seen with venlafaxine and duloxetine, atypical antidepressants that block serotonin reuptake like the SSRIs. 

It appears that SSRls and bnpropion are less likely than TCAs to indnce mania. Venlafaxine, perhaps becanse of its dnal effects on serotonin and norepinephrine like the TCAs, also appears to increase the likelihood of switching into mania. Rarely, if ever, shonld an antidepressant be nsed in bipolar patients withont concomitant treatment with a mood stabilizer. 

Newer Generation Antidepressants. All SSRIs have been shown effective in the treatment of panic disorder. Of these, flnoxetine (Prozac), paroxetine (Paxil), and sertraline (Zoloft), as well as the SNRI venlafaxine ER (Effexor XR), have received FDA approval for the treatment of panic disorder. Because they are safer and easier to tolerate, SSRls/SNRls have largely supplanted the MAOIs and TCAs as standard treatments (along with benzodiazepines) for panic disorder. 

SSRls and SNRIs. The SSRl antidepressants, together with venlafaxine, have replaced the benzodiazepines as treatments of choice for GAD. Paroxetine and escitalopram are FDA approved for GAD, though it is generally believed that all SSRls and SNRIs are effective for GAD. Similar to the TCAs, SSRIs/SNRIs appear to be most effective for the intrapsychic symptoms of GAD but less effective than benzodiazepines for the somatic manifestations of the disorder. 

A controlled trial of duloxetine (Cymbalta)—like venlafaxine a dual serotonin-norepinephrine reuptake inhibitor—in the treatment of GAD is currently underway. Anecdotal data suggests that nefazodone (Serzone) and mirtazapine (Remeron) may be effective in the treatment of GAD, though no controlled data is available. In addition, recent concerns regarding nefazodone and liver toxicity have limited this medication s utility. Please refer to Chapter 3 for more information regarding these antidepressants. 

Atypical Antidepressants. Preliminary open label studies suggested that ven-lafaxine and trazodone might be effective for OCD. However, controlled studies have not yet been completed for venlafaxine, and a controlled study of trazodone (100-200 mg/day) did not find it an effective treatment for OCD. 

Nortriptyline (Pamelor). A recent study suggested that the tricyclic antidepressant nortriptyline, like bupropion, is effective in the treatment of smoking cessation. Nortriptyline does not have any significant effect on dopamine reuptake activity, but it does increase norepinephrine availability. Like bupropion, nortriptyline may therefore reduce the physical symptoms of nicotine withdrawal. Because nortriptyline carries the danger of lethality in overdose and has the unfavorable side effect profile of the tricyclics, we do not recommend its use for smoking cessation. However, it does raise the question as to whether other newer antidepressants that increase norepinephrine activity (e.g., venlafaxine, mirtazapine, duloxetine) may also prove to be effective treatments for nicotine withdrawal. 

If depression is a problem, many clinicians prefer an antidepressant as an augmentation strategy. Because of the problems mentioned earlier, most now avoid using TCAs to treat ADHD. Bupropion, SSRIs, and venlafaxine are viable alternatives, and may add to the effect of the stimulant. Bupropion and venlafaxine are believed to offer some additional improvement in attention. SSRIs may be more likely to improve impulsivity. Each should be started at a low dose and increased gradually. None of these are approved for use in children however. 

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