Antidepressants serotonin/noradrenaline reuptake inhibitor

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). 

The most commonly used therapies for anxiety and depression are selective serotonin reuptake inhibitors (SSRIs) and the more recently developed serotonin noradrenaline reuptake inhibitors (SNRIs). SSRIs, which constitute 60% of the worldwide antidepressant and antianxiety market, are frequently associated with sexual dysfunction, appetite disturbances and sleep disorders. Because SSRIs and SNRIs increase 5-HT levels in the brain, they can indirectly stimulate all 14 serotonergic receptor subtypes [2,3], some of which are believed to lead to adverse side effects associated with these drugs. Common drugs for short-term relief of GAD are benzodiazepines. These sedating agents are controlled substances with addictive properties and can be lethal when used in combination with alcohol. The use of benzodiazepines is associated with addiction, dependency and cognitive impairment. 

Many antidepressant drugs have pronounced effects on sleep. Several tricyclic compounds (amitriptyline and others) have sedative actions while others (imipramine and others) are less sedative or even stimulant. Monoamine oxidase inhibitors (MAOIs) have central stimulant effects and may cause insomnia. Specific serotonin reuptake inhibitors (SSRls) and combined serotonin, noradrenaline reuptake inhibitors (SNRIs) can also cause insomnia. 

Venlafaxine and milnacipran are two members of a new class of antidepressants that have selective effects on the reuptake of both serotonin and noradrenaline—serotonin noradrenaline reuptake inhibitors (SNRIs). In theory, based on the findings of B. M. Baron and colleagues [1988 and of J. C. Nelson and colleagues (1991), the combination of these two pharmacological actions should be associated with superior efficacy either in terms of rapid onset of action or extra efficacy at the end of treatment. 

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. 

Elafax Venlafaxina Venlafaxine Venlafaxinum Venla-fexine, A serotonin noradrenaline reuptake inhibitor. Used as an antidepressant. Crystals mp n102-104° [(-)-fbrm)] [a]8 -27.1" (c = 1.04 in 95% EtOH) [W-fbrm] [a]85= f27.6 (c = 1.07 in 95% EtOH). Am. Home Products Wyetti-Ayerst Labs. 

Noradrenaline transporters (NAT) are localized in the presynaptic plasma membrane of adrenergic nerve terminals. They belong to a family of proteins with 12 putative transmembrane proteins which are responsible for recycling of released neurotransmitters (noradrena-line/adrenaline, dopamine, serotonin, amino acid transmitters) back into the presynaptic nerve ending. Noradrenaline transporters can be blocked by a number of different antidepressant drags, including tricyclic antidepressants (e.g. desipramine) and selective noradrenaline reuptake inhibitors (e.g. reboxetine). 

Many neurotransmitters are inactivated by a combination of enzymic and non-enzymic methods. The monoamines - dopamine, noradrenaline and serotonin (5-HT) - are actively transported back from the synaptic cleft into the cytoplasm of the presynaptic neuron. This process utilises specialised proteins called transporters, or carriers. The monoamine binds to the transporter and is then carried across the plasma membrane it is thus transported back into the cellular cytoplasm. A number of psychotropic drugs selectively or non-selectively inhibit this reuptake process. They compete with the monoamines for the available binding sites on the transporter, so slowing the removal of the neurotransmitter from the synaptic cleft. The overall result is prolonged stimulation of the receptor. The tricyclic antidepressant imipramine inhibits the transport of both noradrenaline and 5-HT. While the selective noradrenaline reuptake inhibitor reboxetine and the selective serotonin reuptake inhibitor fluoxetine block the noradrenaline transporter (NAT) and serotonin transporter (SERT), respectively. Cocaine non-selectively blocks both the NAT and dopamine transporter (DAT) whereas the smoking cessation facilitator and antidepressant bupropion is a more selective DAT inhibitor. 

Taken together, the efficacy of antidepressants covers the spectrum of anxiety disorders, although there are important differences between drugs in the group (Table 3). Several new antidepressants have been marketed since the SS-RIs venlafaxine and mirtazapine are discussed later (Sects. 3.2.1.2 and 3.2.1.4) nefazodone, a serotonin reuptake inhibitor and postsynaptic 5-HT2 blocker showed promise in early studies but was recently withdrawn by its manufacturers reboxetine, a noradrenaline reuptake inhibitor (NARI) showed benefits in panic disorder in one published study (Versiani et al. 2002) and further evidence of its anxiolytic efficacy is awaited. 

Although the efficacy of tricyclic antidepressants in the treatment of unipolar depression is beyond reproach, the side-effect profile of these agents makes them less desirable as first-line therapeutic agents. Introduction of selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, paroxetine, sertraline, citalopram and fluvoxamine in the past decade has revolutionized the treatment of depression universally. The side-effect profile of SSRIs, such as nausea, diarrhea and sexual dysfunction, is considerably more benign than that of tricyclic drugs. Multiple controlled trials have proven the efficacy of SSRIs vs. placebo (Nemeroff, 1994). Recently, a number of SNRIs (serotonin and noradrenaline reuptake inhibitors) and so-called atypical antidepressants have been marketed that may have additional advantages over SSRIs, such as more rapid onset of action (venlafaxine. mirtazapine) and low sexual side-effect potential ( bupropion, nefazodone). Additionally, it appears that venlafaxine may be more efficacious in cases of treatment-refractory depression (Clerc et al., 1994 Fatemi et al., 1999). Finally, in a recent report (Thase et al., 2001),... 

Milnacipran (Pierre Fabre), an equipotent serotonin and noradrenaline reuptake inhibitor, was launched in 1997 as an antidepressant and was licensed for development for the treatment of fibromyalgia and related chronic pain disorders in 2001. It is currently in late preclinical development. 

The symptoms experienced by this patient were typical of venlafaxine and SSRI withdrawal (although they could also be experienced after sudden withdrawal of tricyclic antidepressants). The fact that they were relieved by a serotonin but not a noradrenaline reuptake inhibitor suggests that venlafaxine-induced withdrawal symptoms are mediated by serotonergic mechanisms. 

Within each class or subclass drugs are listed in order of frequency of prescription in the United Kingdom (1997 data). Abbreviations RIMA—reversible inhibitor of monoamine oxidase NaRI—noradrenaline reuptake inhibitor SNRI—serotonin and noradrenaline reuptake inhibitor NaSSA—noradrenaline and specific serotonergic antidepressant. 

Category Antidepressant Noradrenaline reuptake inhibitor Serotonin reuptake inhibitor Half-life 8-17 hours... 

This group includes compounds with actions on a range of neurotransmitter systems. Their antidepressant efficacy is mediated by reuptake inhibition of serotonin and noradrenaline, although side-effects such as sedation may also be useful. Their use in anxiety disorders is supported by a long history of clinical experience and a reasonable evidence base from controlled trials. Studies support the use of clomipramine (a potent serotonin reuptake inhibitor) in panic disorder and OCD (Lecrubier et al. 1997 Clomipramine Collaborative Study Group 1991), of imipramine in panic disorder and GAD (Cross-National Collaborative Panic Study 1992 Rickels et al. 1993), and of amitriptyline in PTSD (Davidson et al. 1993a). No controlled studies support the use of TCAs in social anxiety disorder. 

It has since been assumed that this is the therapeutic action of tricyclic antidepressants, which are sometimes referred to as monoamine reuptake inhibitors or MARIs. However the exact significance of this reuptake process is unknown, especially as the tricyclic antidepressants have numerous other actions and influence, directly or indirectly, almost all neurotransmitters, many neuropeptides and most hormones (Khan 1999). Further studies of reuptake by heart muscle preparations showed that chlorpromazine was a stronger reuptake inhibitor than imipramine and not all the tricyclic antidepressants had this action (Lahti Maickel 1971). In addition, it has not been possible to demonstrate that reuptake inhibition is actually correlated with increased availability or activity of noradrenalin or serotonin. In fact most evidence suggests that tricyclic drugs reduce levels of noradrenalin (Frazer Mendels 1977 Heydorn, Frazer, Mendels 1980 Schildkraut, Winokur, Applegate 1970). 

Specific serotonin reuptake inhibitors, as the class name implies, act predominantly by preventing serotonin reuptake and have more limited effects on noradrenaline reuptake. Tricyclic antidepressants in general inhibit noradrenaline reuptake, but effects on serotonin reuptake vary widely desipra-mine and protriptyline have minimal potential for raising serotonin concentrations, whereas clomipramine possesses a greater propensity for blocking serotonin reuptake than for noradrenaline. The... 

Most antidepressants in clinical use today act by enhancing the neurotransmission of serotonin [5-hydroxytryptamine (5-HT)], norepinephrine [NE noradrenaline (NA)], or both. They do so either by blocking the reuptake (transport) of neurotransmitter, blocking the metabolism of neurotransmitter [i.e., monoamine oxidase (MAO) inhibitors], or by direct action on a neurotransmitter receptor. Hence, the antidepressants can be classified on the basis of their putative mechanisms of action (Table 8.2 and Figs. 8.1-8.4). Agents that block neurotransmitter reuptake can be further divided into those that are non-selective (e.g., tricyclic antidepressants with mixed action), serotonin-selective reuptake... 

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