Acetylcholinesterase inhibitors in treatment-resistant psychotic depression

Abstract

Dopamine receptor antagonists can be effective in psychotic depression but response is not assured. Visual hallucinations may arise from a dysregulation of brain cholinergic systems and acetylcholinesterase inhibitors (AChEIs) can treat such hallucinations in dementia with Lewy bodies (DLB). AChEIs have been used in schizophrenia with some success but their efficacy and tolerability in psychotic depression is unclear. This striking case illustrates AChEIs specifically targeting multimodal hallucinations in treatment-resistant depression. To our knowledge it is the first case report to do so. It highlights the value of delineating psychopathology when considering novel interventions. This case also shows the idiosyncratic nature of side effects and the importance of pursuing different drugs within class.

Case report

Mr M, a 53-year-old White man, had a 25-year history of recurrent, refractory psychotic depression (World Health Organization ICD-10 revision F33.3) that necessitated over 30 hospital admissions. Identifiable triggers were lacking and remission rarely achieved. Excepting childhood anxiety, he was well adjusted before first presentation. Drug or Alcohol misuse did not feature. Treatments of adequate dose and duration included: antidepressants from every major class, alone and in combination; lithium and carbamazepine augmentation; antipsychotics (first and second generation, oral and parenteral) including clozapine, which was stopped due to neutropenia; numerous electroconvulsive therapy (ECT) courses, approximating 600 stimulus deliveries; psychosurgery twice (bilateral anterior capsulotomy in 1996 and anterior cingulotomy in 1999), both producing unsustained responses. Postsurgical absence seizures responded to lamotrigine, but his depression did not. He remained out of hospital periodically with the support of his family and a combination of regular medication, as required chlorpromazine and maintenance ECT.

In July 2012, he was admitted electively during maintenance ECT (135 bilateral stimulus deliveries) whilst taking nortriptyline (300 mg daily), amisulpride (300 mg daily), chlorpromazine (300 mg daily) and lamotrigine (100 mg daily). ECT caused marked cognitive impairment but when stopped, in November 2012, his psychotic depression worsened. He described – with horror – seeing and hearing a “foul-smelling dark man” and could not understand why others did not. This multimodal hallucination was mood congruent, and involved threats to kill the patient’s family unless he committed suicide. He often mistook the ward for his home, required physical contact to ensure that staff were ‘real’ and had vivid dreams of being burned or drowned.

Rivastigmine was prescribed (4.2 mg/day transdermal patch) off-licence in January 2013. His hallucinations lessened and resolved fully within a month; his mood improved concurrently. Drugs with anticholinergic properties were withdrawn during this period. Regrettably, intolerable side effects emerged: sialorrhoea, uncontrolled by hyoscine or ipratropium bromide 0.03% spray, resulted in aspiration pneumonia. Donepezil (10 mg daily) was prescribed in May 2013 and although the drug was better tolerated, his hallucinations and low mood remained. In August, rivastigmine was re-started with a view to countering sialorrhoea as early as possible with oral ipratropium bromide. This worked well but the patient requested a medication change due to oral pain, headache and nausea unresponsive to increased regular chlorpromazine. In November 2013 the N-methyl-D-aspartate receptor antagonist memantine (up to 20 mg once daily) was prescribed but, despite an initial improvement in symptoms, there was a suboptimal response after a 10-week trial. Galantamine (4 mg daily) was then prescribed and tolerated with good therapeutic effect in January 2014 and the patient was discharged home within a month. Other than brief episodes of mild depression he remained largely symptom free for 18 months, whilst progressively withdrawing chlorpromazine, but subsequently relapsed despite increasing galantamine to 8 mg daily. He was switched to rivastigmine for 2 weeks and responded. Following symptom resolution (and the emergence of sialorrhoea) he was returned to maintenance galantamine. He has since remained in partial remission. (The patient provided written informed consent for his case to be written up and published in a peer-reviewed journal.)

Discussion

Response rates to dopamine receptor antagonists in psychotic depression are suboptimal. ¹ Whilst favourable results have emerged for AChEIs in schizophrenia, ² their efficacy and tolerability in psychotic depression remain opaque. Our patient experienced marked therapeutic and adverse effects with AChEIs. Dysregulated brain cholinergic systems have been suggested to lead to visual hallucinations ³ which AChEIs can treat effectively in DLB. ⁴ However, our patient’s response is unlikely to be due to an underlying DLB, as his presentation was stable over decades without overt parkinsonism and cognition was preserved on recovery. Furthermore his adverse effects were more marked than usual in DLB, perhaps reflecting a different underlying pathophysiology. The resolution of hallucinations is likely attributable to procholinergic effects alongside incremental improvements from the removal of anticholinergic drugs, although his partial response to chlorpromazine and clozapine count against this. There is a relative dearth of evidence for the effectiveness of AChEIs in psychosis and the studies that have been conducted^5,6 have not investigated multimodal hallucinations. Xanomeline, a selective muscarinic receptor agonist, has been associated with significant improvements in Positive and Negative Syndrome Scale (PANSS) scores compared with placebo. ⁷ Meanwhile, a Cochrane review ² demonstrated benefit from acetylcholinesterase inhibitors versus placebo when added to antipsychotics in patients with schizophrenia. Both PANSS and depressive symptom scores improved but findings were limited by the small number of studies. AChEIs have been trialled in the elderly with mild cognitive impairment and depression, hypothesizing that improving cognition would improve mood but finding that fewer patients entered remission. ⁸ However, this trial did not specifically examine visual hallucinations in those with depression. Targeting cholinergic systems could be a future avenue for visual hallucinations in affective disorders, but clinicians should be vigilant for disproportionally severe adverse effects. Vortioxetine, a novel multimodal antidepressant with procholinergic effects, ⁹ may prove to be specifically efficacious in such presentations.