The return of fixed combinations in psychiatry: fluoxetine and olanzapine combination

Abstract

Fixed combination psychotropics, such as a combination of a tricyclic and a typical antipsychotic, were widely prescribed a generation ago. These products were plagued by a number of problems, including serious side effects, which caused them to fall out of favor. More recently, a fixed combination of the atypical antipsychotic olanzapine and the serotonin selective reuptake inhibitor (SSRI) fluoxetine has been approved in the US for the treatment of bipolar I depression. Although the combination produced a robust clinical response relative to placebo or olanzapine alone, the response from practitioners has been mixed. The reasons for this are likely to be varied. Some practitioners who remember the earlier era of fixed combinations may simply be resistant to using products of this type. Moreover, the two constituents are available and many clinicians prescribe them independently. Finally, adverse events associated with olanzapine may make practitioners hesitant. For example, weight gain is a common side effect with olanzapine, and may be associated with hyperlipidemia or type II diabetes. Aggressive management of this problem appears to be helpful in preventing or reversing weight gain. It is not clear how weight gain is going to impact the uptake of this effective treatment.

The involvement of GABAA receptor in the molecular mechanisms of combined selective serotonin reuptake inhibitor-antipsychotic treatment

“…These include methodological issues such as distinguishing primary and secondary negative symptoms, and uncertainty whether equally effective antidepressants of the SSRI class have similar effectiveness as augmenting agents for negative symptoms. The combination of SSRI and antipsychotic has also been reported useful in patients with resistant obsessive-compulsive and affective disorders (Bloch et al 2006 ;Bobo & Shelton, 2009 ;Shelton, 2006).…”

The administration of olanzapine and fluoxetine has synergistic effects on intracellular survival pathways in the rat brain

“…Preclinical and clinical studies have shown positive effects using a combination of the antidepressant fluoxetine (FLX), and the antipsychotic, olanzapine (OLZ) (Shelton, 2006;Tohen et al, 2010;Bobo and Shelton, 2010;Vieta et al, 2010;Agostinho et al, 2011a,b). The combination of OLZ and FLX might have an impact on synaptic transmission, which in turn could lead to a differential regulation of intracellular survival pathways relevant for therapeutic activity (Maragnoli et al, 2004).…”

“…FLX alone or in combination with amantadine, an N-methyl-D-aspartate (NMDA) receptor antagonist, increased mRNA BDNF in the cerebral cortex (Rogóz et al, 2008). The combination of antidepressants within various pharmacological groups is used in the clinical environment to improve therapy (Shelton, 2006;Tohen et al, 2010). In basic experiments, the association of antidepressants with other drugs has showed a better effect than when used alone (Roman et al, 2009;Rogóz, 2010).…”

“…Following this route of study, the combination of the antipsychotic olanzapine (OLZ), and of the antidepressant fluoxetine (FLX) have been used. Very recently, the combination of the two drugs was approved by the Food and Drug Administration (FDA) for the treatment of depressive episodes associated with bipolar disorder (Shelton, 2006;Tohen et al, 2010;Bobo and Shelton, 2010;Vieta et al, 2010). In fact, Shelton et al (2001) showed in a controlled study where subjects with treatmentresistant depression received OLZ alone, FLX alone, or a combination of both, that the combination was associated with significantly greater and faster improvement than was possible with either drug when used alone.…”

Chronic treatment with serotonin reuptake inhibitor antidepressant (SSRI) combined with an antipsychotic regulates GABA-A receptor in rat prefrontal cortex

“…Combinations of SSRI and antipsychotic may also be useful in treatment-resistant obsessive-compulsive disorder and depression (Bloch et al 2006;Bobo and Shelton 2009;Shelton 2006). Most controlled studies of add-on SSRI examined augmentation of typical antipsychotics, but evidence from open studies and case reports indicates that SSRI augmentation of atypical antipsychotics such as olanzapine, risperidone, or clozapine can also be useful (see Silver et al 2003b for discussion).…”