Antipsychotic-induced brain atrophy – Is lithium the answer in bipolar disorder?

To the Editor

We note the recent debate piece (Bastiampillai et al., 2018) highlighting concerns about the potential implications of prescribing antipsychotic medication in paediatric populations, due to the potential risks of antipsychotic-induced brain atrophy. Worldwide antipsychotic medications are increasingly being prescribed for the maintenance treatment of bipolar affective disorder (BPAD) in preference to mood-stabilising medication like lithium. Lithium use is declining despite being the gold standard treatment for the maintenance phase of BPAD.

Both animal and human studies suggest that long-term use of antipsychotic medications can lead to brain atrophy and volume loss (Ho et al., 2011), while lithium and valproate may have neuroprotective effects (Chiu et al., 2013). The seminal study by Ho et al. (2011) demonstrated that increasing dose and duration of antipsychotic medication was associated with generalised brain tissue volume reduction in multiple subregions while also controlling for potential confounding factors like illness duration, severity and substance misuse.

BPAD is potentially a neurodegenerative illness; therefore, the neuroprotective role of medications should be an important consideration. A number of animal studies have shown that the use of lithium and valproate appeared to prolong cell survival and decrease neurodegeneration while also enhancing neurogenesis. A review by Chiu et al. (2013) highlighted that the neuroprotective actions arise from interactions with different signalling molecules including brain-derived neurotrophic factor, glial-cell line-derived neurotrophic factor and anti-apoptotic proteins.

Previous studies specially investigating the impacts of lithium on cognitive functioning in BPAD found that memory and cognition scores were higher in patients treated with lithium compared to other medications (Chiu et al., 2013). BPAD patients treated with lithium had increased grey matter volumes in whole brain, anterior cingulate and the cortex (Chiu et al., 2013). Of particular note, limbic structures, including the hippocampus, important in emotional regulation also demonstrated volume increases (Chiu et al., 2013).

It is our view that given lithium’s well-established efficacy for BPAD maintenance treatment, combined with its neuroprotective effects, its declining worldwide use is a concern. This becomes more important in the light of emerging evidence of potential neurotoxicity of antipsychotic medication, whose usage is increasing despite limited evidence for their long-term efficacy in BPAD. This could be attributed to a possible commercial bias against lithium with pharmaceutical companies aggressively marketing antipsychotic medication. Clinical decision-making about the optimal maintenance treatment of BPAD should therefore also factor various medications’ differential effect on causing either neurogenesis or neurotoxicity.