Anxious depression, defined as major depressive disorder (MDD) accompanied by high levels of anxiety, seems to be difficult to treat with traditional antidepressant monotherapy. The purpose of this study was to assess the efficacy of ziprasidone monotherapy in patients with anxious depression versus non-anxious depression. One hundred and twenty outpatients were enrolled in a 12-week study that was divided into two 6-week periods according to the sequential parallel comparison design. Patients were randomized in a 2:3:3 multi-ratio to receive ziprasidone for 12 weeks, placebo for 6 weeks, followed by ziprasidone for 6 weeks, or placebo for 12 weeks. Efficacy was measured according to the 17-item Hamilton Depression Rating Scale (HRDS-17), Quick Inventory of Depressive Symptomatology Self-Rated (QIDS-SR). Anxious depression was defined as a score of ≥7 on the HDRS-17 anxiety/somatization subscale. In phase I and II, ziprasidone monotherapy led to no significant changes compared with placebo on the HDRS-17 and QIDS-SR scores in patients with both anxious and non-anxious depression. In the pooled analysis, ziprasidone monotherapy also produced no significance on the HDRS-17 (Z = 0.25, P = 0.80) and QIDS-SR (Z = 0.43, P = 0.67) in patients with anxious depression. In conclusion, treatment with ziprasidone monotherapy may produce no significant improvement compared with placebo in patients with in anxious depression.
Major depressive disorder (MDD) consists of heterogeneous subtypes that are related to treatment outcome (Vrieze et al., 2014). Anxious depression, is defined as MDD accompanied by a high level of anxiety, nervousness, and the somatic correlates of these states (Fawcett and Kravitz, 1983), and is found in about half of MDD patients (Fava et al., 2004). The DSM-5 classification added ‘anxious distress specifier’ to MDD diagnosis (American Psychiatric Association, 2013). The presence of anxious depression has been associated with greater severity of depressive illness and functional impairment (Joffe et al., 1993), higher suicide risk (Tollefson et al., 1994), and poorer response to antidepressants, including significantly lower response and remission rates, more frequent and intense side effects, despite changes in medication or augmentation techniques (Fava et al., 2008, Papakostas et al., 2012a, Papakostas and Larsen, 2011 and Seo et al., 2011).
Ziprasidone is an atypical antipsychotic with several pharmacologic properties suggestive of antidepressant actions, including 5-HT2A, 5-HT2C, 5-HT7, 5-HT1B/D and α2 antagonism and dopaminergic receptor antagonism. It additionally inhibits norepinephrine and serotonin reuptake (Nemeroff et al., 2005 and Stahl and Shayegan, 2003). Ziprasidone possesses a high 5-HT2A/D2 affinity ratio (Richelson and Souder, 2000 and Tatsumi et al., 1999) and acts as a 5-HT2A receptor antagonist. Ziprasidone additionally acts as a 5-HT1A receptor partial agonist. 5-HT1A receptor partial agonists have demonstrable antianxiety and antidepressant properties (Robinson et al., 1990). Ziprasidone appears to be suited for study as monotherapy in anxious depression, since it has a unique affinity for several monoaminergic receptors and transporters. However, no previous clinical trials have examined the effect of ziprasidone monotherapy in anxious depression patients.
The purpose of the present study was to examine the comparative efficacy of ziprasidone monotherapy for treatment of patients with anxious depression and non-anxious depression.
In conclusion, the present study suggested that treatment of anxious depression with ziprasidone monotherapy did not show any statistically significant advantage in efficacy over placebo. Future studies are needed to replicate these findings, and include adequate dosing and study duration.
