Selective serotonin reuptake inhibitors with stimulants

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. 

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. 

Clear abnormalities of the dopamine system have not been identified in the periphery or the brain of OCD patients. Nevertheless, repetitive stereotypies and OCD-like behaviors can be produced in humans by the administration of exogenous D2 agonist or stimulants, which suggests that the dopaminergic system may be involved in some way in OCD. Conversely, antipsy-chotics can be used adjunctively in the treatment of selective serotonin reuptake inhibitor (SSRl)-resistant OCD patients with a definite benefit in a significant proportion of patients. 

Injection of botulinum toxin A at the site of problematic tics is sometimes helpful. Treatment of any associated attention deficit disorder (eg, with clonidine patch, guanfacine, pemoline, methylphenidate, or dextroamphetamine) or obsessive-compulsive disorder (selective serotonin reuptake inhibitors or clomipramine) may be required. Bilateral thalamic stimulation is sometimes worthwhile in otherwise intractable cases. 

Atomoxetine, bupropion, and TCAs are second-line alternatives to the stimulants for treatment of ADHD in children, teens, and adults. The potential benefits of these agents in comparison with stimulants include reduced risk of abuse and somewhat lower potential for sleep disturbance. TCAs are the most dangerous in overdose and pose the greatest risk for cardiovascular side effects. The monoamine oxidase inhibitor tranylcypromine is effective but used infrequently due to the potential for dangerous drug and dietary interactions. Selective serotonin reuptake inhibitors (SSRIs) are not effective for ADHD. ... 

Most prominent among the psychotropics that enhance serotonergic transmission are the selective serotonin reuptake inhibitors (SSRIs), which may induce sexual dysfunction in as many as 50-75% of patients, in part by activation of central 5-HT2 receptors. Antidepressants that antagonize the 5-HT2 receptor, such as mirtazapine and trazodone, cause fewer sexual side-effects compared with the SSRIs. Stimulation of the 5-HTia receptor facilitates sexual functioning, while activation of the 5-HTib,id and 5-HTic receptors inhibits... 

Sedation Sedation is a common CNS effect of tricyclic drugs (although less so with protriptyline and desipramine) and of most heterocyclic agents (Table 30-2). MAO inhibitors, selective serotonin reuptake inhibitors, and bupropion are more likely to cause CNS-stimulating effects. 

Serotonin (5-hydroxytryptamine) is produced from tryptophan by the indoleamine pathway. Serotonin is important for a feeling of wellbeing, and a deficiency of brain serotonin is associated with depression. The selective serotonin reuptake inhibitors (SSRIs) are a successful class of antidepressive drugs that prolong the presence of serotonin in the synaptic cleft, thereby stimulating synaptic transmission in neurones that produce a sense of euphoria. 

One of the main issues related to tramadol is the fact that it blocks serotonin reuptake and may cause serotonin syndrome in susceptible patients. Serotonin syndrome is characterized by neurological and cardiovascular stimulation, and can lead to seizures and death. Risks of developing serotonin syndrome are increased in patients treated with selective serotonin reuptake inhibitors and serotonin and norepinephrine reuptake inhibitors. 

Selective serotonin reuptake inhibitors (SSRIs) are effective antidepressants with fewer side effects than the older tricyclics. However, SSRIs require weeks of treatment before efficacy is observed. This delay in efficacy is believed to be due to stimulation of inhibitory 5-HT1A autoreceptors the onset of antidepressant activity is consistent with a time-dependent desensitization of 5-HT1A autoreceptors. Combining SSRI and 5-HT1A receptor antagonism within one molecule should maximize serotonergic function and result in an immediate increase in synaptic levels of 5-HT in forebrain... 

Although postsynaptic DA agonists and presynaptic Dj autoreceptor antagonists share a common property of enhancing DA transmission, Dj autoreceptor agonists have been developed specifically to block DA transmission as an alternative approach to antipsychotic therapy (Benkert et al. 1992). A variety of such compounds are available (Seyfried and Boettcher 1990), four of which—talipexole, pramipexole, roxindole, and OPC-4392 —have been evaluated as antipsychotics in schizophrenic patients (Benkert et al. 1992). Only roxindole has been tested in depression, and then only in two uncontrolled pilot studies over 4 weeks of treatment (Benkert et al. 1992 M. Kellner et al. 1994). Response rates similar to those of imipramine were observed, with a fast onset of action in some patients. Roxindole s antidepressant action may lie in its ability to selectively stimulate supersensitive postsynaptic Dj receptors, and thereby enhance DA function, or in its additional properties as an inhibitor of serotonin reuptake and as a 5-HT, receptor agonist (Benkert et al. 1992 Seyfried et al. 1989). 

The majority of patients need medication for the two main symptoms. Drugs with CNS-stimulating effects, mostly of the amphetamine type, are used to alleviate excessive sleepiness and sleep attacks. The resulting increased level of vigilance also decreases or abolishes cataplexy in a number of patients. If this is not achieved, tricyclic antidepressants, in the hrst instance, and selective serotonin (5-hydroxytryptamine 5-HT) reuptake inhibitors, in the second instance, can be used to control cataplexy and other rapid-eye-movement sleep-related symptoms. 

In addition to its other functions BH4 enhances the release of dopamine and serotonin in the rat striatum when administered locally through the dialysis membrane. The enhancement of dopamine release persisted even when dopamine biosynthesis or dopamine reuptake was completely blocked, but it was abolished when hlockers of voltage-dependent Na" " or Ca " " channels were administered with BH4. Further experiments using selective inhibitors of tyrosine, TH, and NOS demonstrated that BH4 stimulates dopamine release directly, independent of its cofactor action on TH and NOS, by acting from the outside of neurons. The exact mechanism is not entirely clear but it has been shown that arginine also induces a concentration-dependent increase of dopamine release in the superfusate of rat striatum slices, and that it is dependent on the presence of BH4. ... 

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