Selective serotonin reuptake inhibitors indications

Recent evidence indicates that the 5-HT transporter is subject to post-translational regulatory changes in much the same way as neurotransmitter receptors (Blakeley et al. 1998). Protein kinase A and protein kinase C (PKC), at least, are known to be involved in this process. Phosphorylation of the transporter by PKC reduces the Fmax for 5-HT uptake and leads to sequestration of the transporter into the cell, suggesting that this enzyme has a key role in its intracellular trafficking. Since this phosphorylation is reduced when substrates that are themselves transported across the membrane bind to the transporter (e.g. 5-HT and fi -amphetamine), it seems that the transport of 5-HT is itself linked with the phosphorylation process. Possibly, this process serves as a homeostatic mechanism which ensures that the supply of functional transporters matches the demand for transmitter uptake. By contrast, ligands that are not transported (e.g. cocaine and the selective serotonin reuptake inhibitors (SSRIs)) prevent the inhibition of phosphorylation by transported ligands. Thus, such inhibitors would reduce 5-HT uptake both by their direct inhibition of the transporter and by disinhibition of its phosphorylation (Ramamoorthy and Blakely 1999). 

Markei H, Lee A, Hoimes RD, Domino EF. (1994). LSD flashback syndrome exacerbated by selective serotonin reuptake inhibitor antidepressants in adoiescents. J Pediatrics. Pt 1. 125(5) 817-19. Mascher E. (1967). Psychoiytic therapy Statistics and indications. In Neuropsychopharmacology,... 

TCA, tricyclic antidepressant SSRI, selective serotonin reuptake inhibitor MAOI, monoamine oxidase inhibitor. 0, no effect +, + +, + + + indicate increasing effect. 

The selective serotonin reuptake inhibitors (SSRI) have been used in adults for a wide variety of disorders, including major depression, social anxiety (social phobia), generalized anxiety disorder (GAD), eating disorders, premenstrual dysphoric disorder (PMDD), post-traumatic stress disorder (PTSD), panic, obsessive-compulsive disorder (OCD), trichotillomania, and migraine headaches. Some of the specific SSRI agents have an approved indication in adults for some of these disorders, as reviewed later in this chapter. The SSRIs have also been tried in children and in adults for symptomatic treatment of pain syndromes, aggressive or irritable ( short fuse ) behavior, and for self-injurious and repetitive behaviors. This chapter will review general aspects of the SSRIs and discuss their approved indications in children and adolescents. 

TABLE 22.1 Food and Drug Administration-Approved Indications for Serotonin Reuptake Inhibitor and Selective Serotonin Reuptake Inhibitor Agents... 

The study of TCAs in children with OCD led directly from the use of these medications in adults with similar symptoms. Findings have shown significant advantage with both CMI and DMI over placebo in the treatment of this illness (Flament et al., 1985 deVaugh-Geiss et al., 1992). Clomipramine is the only TCA with a distinct indication from the FDA for the treatment of OCD. Use of TCAs has recently been supplanted by selective serotonin reuptake inhibitor (SSRI) medications that may have a more favorable side effect profile. 

Preliminary findings indicate that the addition of fluoxetine may increase response or benefit treatment-resistant schizophrenic patients ( 367, 368 and 369). Further, deficit symptoms seemed to improve in some patients, supporting a possible role for 5-FIT2 hypersensitivity as the underlying mechanism 370). Care must be taken to monitor plasma levels of antipsychotics, which may rise when combined with this selective serotonin reuptake inhibitor (SSRI) or other related antidepressants due to their ability to inhibit various CYP 450 isoenzymes. 

Despite the diagnostic challenges that remain in trying to understand the nature of MDD in children and adolescents, advances in its treatment has progressed considerably since the last edition of this textbook. Over this interval, selective serotonin reuptake inhibitors (SSRIs) have superseded TCAs as the treatment of first choice based both on efficacy and safety considerations. As in adults, specific psychotherapies (cognitive therapy, cognitive-behavioral therapy, and interpersonal therapy) may be as effective as antidepressant medication, at least in mild to moderate depression in children and adolescents ( 111, 112). Also, evidence indicates that depression in children and adolescents may be more influenced than is depression in adults by psychosocial variables such as peers and family, as well as other environmental factors (113). 

The selective serotonin reuptake inhibitors (SSRIs) represent a chemically diverse class of agents that have as their primary action the inhibition of the serotonin transporter (SERT) (Figure 30-3). Fluoxetine was introduced in the United States in 1988 and quickly became one of the most commonly prescribed medications in medical practice. The development of fluoxetine emerged out of the search for chemicals that had high affinity for monoamine receptors but lacked the affinity for histamine, acetylcholine, and adrenoceptors that is seen with the tricyclic antidepressants (TCAs). There are currently six available SSRIs, and they are the most common antidepressants in clinical use. In addition to their use in major depression, SSRIs have indications in GAD, PTSD, OCD, panic disorder, PMDD, and bulimia. Fluoxetine, sertraline, and citalopram exist as isomers and are formulated in the racemic forms, whereas paroxetine and fluvoxamine are not optically active. Escitalopram is the S enantiomer of citalopram. As with all antidepressants,... 

No special indications for particular types of depression have been found for the selective serotonin reuptake inhibitors or other newer antidepressants. The popularity of these drugs, despite their higher cost, is due principally to their greater acceptance by patients. A provocative clinical report that fluoxetine use increased suicidal or aggressive ideation was not supported by subsequent analyses of massive data bases. Suicidal thoughts are part of the depressive syndrome. 

Fluoxetine (Prozac /Lilly), paroxetine (Paxil /GlaxoSmithKilne), and sertraline (Zoloft /Pfizer) are selective serotonin reuptake inhibitors (SSRIs) and are useful in the treatment of depression. These agents potentiate the pharmacological actions of the neurotransmitter serotonin by preventing its reuptake at presynaptic neuronal membranes. In addition to its SSRI properties, venlafaxine (EfFexor /Wyeth-Ayerst) also appears to be a potent inhibitor of neuronal norepinephrine reuptake and a weak inhibitor of dopamine reuptake thereby enhancing the actions of these neurotransmitters as well. Venlafaxine is indicated for use in anxiety and depression. 

Once armed with this understanding, pharmaceutical researchers went back to their labs and developed molecules capable of replicating these effects. Adjusting the structure of the molecules and submitting these new compounds to various tests, they produced the second generation antidepressants, the SSRIs (selective serotonin reuptake inhibitors as their name indicates, they selectively inhibit the reuptake of serotonin from the synapse back into the neuron from which it was originally released) and several others. 

Indications Depression, obsessive-compulsive disorder Category Antidepressant Selective serotonin reuptake inhibitor Half-life 2-3 days... 

Some selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, fluvoxamine, and paroxetine, are potent inhibitors of CYP2D6 activity. Therefore, multiple dosing causes autoinhibition of CYP2D6 and conversion from extensive to slow metabolizer phenotype and from ultrafast to extensive metabolism [16,17]. In the case of fluvoxamine, diflerences in areas under the curve (AUCs) were described after single doses [18,19], whereas multiple doses result in similar AUCs in PMs and EMs, indicating a strong inhibitory effect on CYP2D6 in EMs [20]. 

Selective serotonin reuptake inhibitors (SSRIs) are first-line agents when medications are indicated for BN, because of improved tolerability and safety, but they do not have superior efficacy compared with other antidepressant classes. The dose of fluoxetine in BN is higher (60 mg/day) than the dose usually used in depression. 

If antidepressant is indicated, start at a low dose, and use a selective serotonin reuptake inhibitor unless there is a medical reason not to do so. 

Escitalopram is a selective serotonin reuptake inhibitor that inhibits the CNS neuronal nptake of serotonin, potentiating serotonergic activity. It is indicated in the major depressive disorders and generalized anxiety. 

Few data are available about paroxetine interactions with MAOIs, even though they might be similar to those of other selective serotonin reuptake inhibitors (SSRIs). Clinically significant or severe interactions have not been found to date. Administered together in patients with depression, moclobemide and paroxetine or fluoxetine appeared to produce adverse effects indicative of potentiated serotonergic activity. 

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