Selective serotonin reuptake with antipsychotics

There is, however, a unique risk in the bipolar form that antidepressant treatment may trigger a switch into mania. This may occur either as the natural outcome of recovery from depression or as a pharmacological effect of the drug. Particular antidepressants (the selective serotonin reuptake inhibitors) seem less liable to induce the switch into mania than other antidepressants or electroconvulsive therapy. Treatment for mania consists initially of antipsychotic medication, for instance the widely used haloperidol, often combined with other less specific sedative medication such as the benzodiazepines (lorazepam intramuscularly or diazepam orally). The manic state will usually begin to subside within hours and this improvement develops further over the next 2 weeks. If the patient remains disturbed with manic symptoms, additional treatment with a mood stabilizer may help. 

A countrywide study based on the national medicinal preparations register in Denmark showed that in 1997, 0.3% of the group aged 0-19 years was under treatment with either antipsychotics, psychostimulants, or antidepressants (Sorensen, 1998). The largest use was found among those aged 16-18 years, for whom selective serotonin reuptake inhibitor (SSRl) preparations comprised 90% of the antidepressants. 

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. 

Metabolic and cardiovascular adverse events were further studied by the same authors in the same sample of children and adolescents [7 ]. Compared with the controls, the treated cohort had a higher prevalence of obesity (OR = 2.1), type 2 diabetes mellitus (OR = 3.2), cardiovascular conditions (OR = 2.7), and orthostatic hypotension (OR = 1.6). In the treated cohort, those who had been exposed to multiple antipsychotic drugs had a significantly higher risk of incident obesity/weight gain (OR = 2.3), type 2 diabetes mellitus (OR = 2.4), and dyslipidemia (OR = 5.3). Incident cardiovascular events were more likely with the use of conventional antipsychotic drugs (OR = 4.3) and mood stabilizers (OR = 1.3). Incident orthostatic hypotension h os more prevalent in those co-prescribed selective serotonin reuptake inhibitors (OR = 1.8) and mood stabilizers (OR = 1.3). 

Haloperidol (Haldol), risperidone (Risperdal), loxapine (Loxitane), ziprasidone (Geodon), quetiapine (Seroquel), clozapine (Clozaril), aripiprazole (Abilify), and thioridazine (Mellaril) are targeted in this solid phase extraction (SPE), liquid chromatography— tandem mass spectrometry (LC-MS/MS) method. Both 9-hydroxy-risperidone (Paliperiodone), an equipotent metabolite, and mesoridazine (Serentil) are also included in this method as they are pharmacologically active major metabolites of risperidone and thioridazine, respectively (4). Olanzapine (Zyprexa) can be quantified with this instrument method however, the extraction method is a liquid-liquid basic extraction (see Note 1). Due to the subsequent administration of antidepressants in conjunction with antipsychot-ics, this method can also be used for many of the common antidepressants, including the selective serotonin reuptake inhibitors (SSRIs) (see Note 2). 

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). 

Sedatives or anticonvulsants (e.g., carbamazepine, oxcarbazepine, phenobarbital, and pheny-toin, but not valproate) that induce CYPs (see Chapter S) can enhance the metabolism of antipsychotic and many other agents (including anticoagulants and oral contraceptives), sometimes with significant clinical consequences. Conversely, selective serotonin (5-HT) reuptake inhibitors including fluvoxamine, fluoxetine, paroxetine, venlafaxine, sertraline, and nefazodone (see Chapter 17) compete for these enzymes and can elevate circulating levels of neuroleptics. 

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