# 32 - Acute treatment

# Acute treatment

362
The Maudsley® Prescribing Guidelines in Psychiatry
CHAPTER 3
Psychotic depression
Psychotic depression represents a severe manifestation of depression. It is diagnosed in 
people experiencing a major depressive illness accompanied by psychotic symptoms 
such as hallucinations and/or delusions. It can occur in the context of both MDD and 
bipolar disorder. Psychotic depression has a lifetime prevalence of 1%.1 However, it is 
often under-­diagnosed and is commonly not adequately identified despite requiring a 
different treatment approach.2,3 When compared with non-­psychotic depression, psychotic depression is associated with greater illness severity, impairment and episode 
duration.4 Once an individual has experienced psychotic symptoms during a depressive 
episode there is a risk of their recurrence in future episodes.4,5 Furthermore, long-­term 
outcomes are generally poorer for psychotic than non-­psychotic depression.6–8 Patients 
with psychotic depression may also have a poorer response to combined pharmacological and psychological treatment than those with non-­psychotic depression.9 People 
with psychotic depression are much more likely than those with non-­psychotic depression to attempt and complete suicide.8,10
Acute treatment
While it is important to acknowledge that no treatments have been granted regulatory 
approval specifically for psychotic depression,11 there is sufficient evidence to guide 
treatment decisions. Oliva and colleagues12 conducted a systematic review and network 
meta-­analysis of pharmacological treatments for psychotic depression in 2024. This 
network meta-­analysis included 14 randomised controlled trials including patients in 
the acute phase of their illness. It found that, compared with placebo, the combination 
of an SSRI and an SGA, particularly fluoxetine and olanzapine, resulted in the highest 
proportion of participants with a treatment response.12 Overall, this specific combination also showed a good balance between efficacy and tolerability and specifically 
improved depressive symptom scores compared with placebo.12 The network meta-­
analysis concluded that this treatment option is the most appropriate choice in people 
with psychotic depression.12
When different treatment options were compared directly, a combination of antipsychotics and antidepressants was also found to have greater efficacy than monotherapy 
with either antipsychotic or antidepressant alone.12 Prior meta-­analyses support this 
outcome, although they were not able to provide specific recommendations on individual drugs because of methodological restrictions.13,14 UK NICE guidance from 2022, 
although written some time before the latest network meta-­analysis, also advocates this 
approach.11,15
The 2024 network meta-­analysis also compared monotherapies and found that TCAs 
(amoxapine and imipramine) were more efficacious than serotonin–noradrenaline 
reuptake inhibitors (SNRIs; venlafaxine) and noradrenergic and specific serotonergic 
reuptake inhibitors (mirtazapine) when overall treatment response was assessed.12
It is important to consider that this network meta-­analysis only included patients in 
the acute phase of their illness. Continuation and maintenance studies were excluded. 
In addition, it only included studies published up to 2013, so drugs used in clinical 
practice more recently could not be examined.