Antipsychotic use and resulting high prolactin levels in acquired brain injury: Impact on cognitive functioning -a case study
A special report co-written by Dr Danielle Desperles-Hughes, consultant clinical psychologist & clinical lead, Dr Martine Stoffels, consultant general adult, old age and rehabilitation psychiatrist, and Eleanor Couch, psychology support worker; all representative of the Avalon Centre, Swindon, Elysium Neurological Services, Elysium Healthcare, UK.
In the management of outcomes following Acquired Brain Injury (ABI), use of antipsychotics is not unusual. Some survivors were started on this class of medication prior to injury to treat pre-existing conditions such as psychosis or depression; for others this type of medication is initiated following ABI to help with symptoms arising from this including mood instability and impulsivity.
For most individuals, medications are initiated by General Practitioners (GP’s) and less frequently community psychiatrists due to their perceived usefulness for managing a wide range of ABI related difficulties.
Broadly speaking, antipsychotics have their clinical effect by influencing the dopamine pathways in the brain to effect symptoms such as hallucinations, delusions and mood. However, antipsychotic medication can equally affect the pathways responsible for cognition, movement, and prolactin secretion which results in potential problematic side effects.
Hyperprolactinaemia, a pituitary secretion syndrome, is characterised by an excess of prolactin in the blood.
High levels of prolactin are associated with:
Changes in menstrual cycle
Bone
loss
Reduced libido
Infertility
While this can occur in people who have a pituitary tumour which secretes high levels of prolactin, during pregnancy and with conditions such as hypothyroidism, for a number of people, high levels of prolactin occur as a result of the use of medication. It is for example present in 70-91% across psychosis patients taking some types of antipsychotic medication (Bostwick et al., 2009).
Under normal circumstances, in the absence of medication, prolactin secretion from the pituitary gland is regulated by dopamine, which inhibits its release and serotonin, which stimulates it. Secretion of prolactin will therefore depend on the balance between these two influences.
With the use of some medications, such as some of those used in the treatment of psychoses, this balance can change, resulting in an increase of prolactin release into the blood stream (Bostwick et al., 2009).
Whilst historically it was thought that the impact of medication on cognition was related to the side effects of antipsychotics, there is emerging evidence that hyperprolactinaemia itself is associated with adverse effects on cognitive function.
Several studies of people with prolactin producing tumours, revealed a negative correlation between prolactin and cognitive performance in domains of reasoning, problem solving and general cognitive ability (Labad, 2019), processing speed (Montalvo et al. 2014), verbal memory and cognitive flexibility (Yao et al. 2018), and attention and working memory (Bala et al. 2022).
Case study
To explore this and demonstrate the effects of raised prolactin on cognitive function of a cognitively vulnerable individual, we present the case of a 26-year-old female who had sustained a traumatic brain injury (TBI).
AS (initials changed for anonymity) was admitted for management of chronic difficulties experienced as a consequence of TBI to the Avalon Centre, Swindon, UK, a neurobehavioral rehabilitation (NbR) unit where a highly specialist clinical team use a transdisciplinary team (TDT) approach to the assessment and management of ABI related difficulties.
The Avalon Centre, Swindon
The Avalon Centre, Swindon
At the age of 6-years, AS was involved in a road traffic accident where she was hit by a motor vehicle.
Injuries received included traumatic subdural hematoma and multiple fractures.
The accident resulted in AS experiencing mild epilepsy and a right sided weakness. She attended mainstream schools and managed to hold a job.
Prior to her current admission she was living reasonably independently with support from a case manager and a carer who had been involved since the age of 12-years.
In the few months prior to admission to the Avalon Centre, concerns were raised about AS’s presentation and safety when living at home. She first came to the attention of mental health liaison services as an adult after taking an overdose.
Six months later she was re-referred to services by her carer due to a decline in her mental state, following the death of a close family member a few months prior.
She began to drink excessively and further attempted to overdose with reported intent of ending her life.
She also began to present as elated in mood and expressed paranoid and grandiose beliefs.
After several failed attempts at support, she was transferred for NBR to address remaining concerns around issues such as impulsivity, changes in interpersonal relationships, information processing and problem solving.
On admission, medications included Olanzapine 15 mg for psychotic symptoms and elated mood, Amitriptyline 20 mg for pain, and Promethazine 25 mg for sleep and agitation.
Following admission, a neuropsychological assessment was completed.
The Test of Premorbid Functioning (TOPF) (Weschler, 2009) was administered to assess AS’s estimated level of functioning prior sustaining her brain injury. Performance on the test and her demographic profile indicated she had previously functioned in the “Average” range.
However, on an assessment of her current global cognitive functioning using the Repeatable Battery for the Assessment of Neuropsychological Status – Version A (RBANS A) (Randolph, 1998) her overall score suggested her current level of cognitive functioning at that time fell in the “Extremely Low” range; below the 1st percentile which means, compared with her peers 99% would have performed better.
At the time of this initial assessment routine blood tests indicated an excessively high prolactin level of 767 (Range 0-530 mlU/L; Serri et al, 2003) even though Olanzapine is not commonly known to be associated with an increase in prolactin.
Therefore, all of AS’s medications were reviewed for their impact on prolactin release, either by affecting dopamine levels or acetylcholine levels in the brain.
A good clinical tool for the latter is the establishment of Anticholinergic Burden (ACB) as increased ACB can result in detrimental effects on cognition.
AS’s total ACB score was 9 (Olanzapine [Score of 3]; Amitriptyline [Score of 3] and Promethazine [score of 3]). A score of 3+ is associated with increased cognitive impairment and increased mortality rates (Boustani et al 2008; Fox et al 2011; NICE Guidance) which led to the discontinuation of both Olanzapine and Promethazine.
Sodium Valproate was also introduced with the goal of stabilising mood, rather than relying on antipsychotics.
It was agreed to repeat cognitive assessment five weeks after these amendments to her medication regime had been completed to assess if medication changes had positively impacted her cognitive function.
On re-examination, the Repeatable Battery for the Assessment of Neuropsychological Status – Version B (RBANS B) demonstrated a marked improvement in AS’s scores following changes in her medication regime (see table 1).
The critical value for statistically significant difference between total scale scores on the two versions is 13.5 [0.05 significance level] therefore the actual discrepancy between tests of 21 is notable. Percentile ranks and Confidence Intervals (CI) are also reported below.
Table 1 – Neuropsychological Assessment Results (Initial vs Repeat Assessment)
|
ASSESSMENT OF COGNITIVE FUNCTIONING |
|||
|---|---|---|---|
|
Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) |
Version A Score |
Version B Scores |
Significant Change? |
|
Immediate Memory |
49 (Ex. Low) <0.1 Percentile; CI (37 – 61) |
85 (Low Average) 16th Percentile; CI (73-97) |
Y |
|
Visuospatial Constructional |
66 (Ex. Low) 1st Percentile; CI (52 – 80) |
78 (Borderline) 7th Percentile; CI (64-92) |
N |
|
Language |
54 (Ex. Low) 0.1 Percentile; CI (39 – 69) |
78 (Borderline) 7th Percentile; CI (63-93) |
Y |
|
Attention |
72 (Borderline) 3rdPercentile; CI (60 – 84) |
88 (Low Average) 21st Percentile; CI (76 – 100) |
Y |
|
Delayed Memory |
40 (Ex. Low) <0.1 Percentile; CI (28 – 52) |
56 (Ex. Low) 0.2 Percentile; CI (44 - 68) |
Y |
|
Total Scale Score ≤69 = "Extremely Low"; 70-79 = "Borderline”; 80-89 = "Low Average"; 90-110 = “Average” |
50 (Ex. Low) <0.1 Percentile; CI (42 – 58) |
71 (Borderline) 3rd Percentile; CI (63 - 79) |
Y |
*CI = confidence scores – scores outside this range are considered statistically significant.
On this reassessment, her scores for immediate memory, language, attention and delayed memory all statistically improved which also resulted in a statistical improvement in her overall scale score.
Whilst there was also a positive change in her Visuospatial / constructional ability, this change was not statistically significant.
When considering the potential causes of such an improvement in cognition on formal testing, given the short time frame of 5 weeks, it is unlikely that this was attributable to spontaneous recovery so long after injury.
Instead, the improvements were attributed to the changes in medication and a reduction in side effect burden.
This highlights the importance of challenging assumptions about diagnosis, and the need to constantly review the severity of conditions through repeat assessments, careful review and analysis of outcome measures and exploration of apparent deteriorations and inconsistencies.
In this case, a careful review of AS’s presentation in comparison to her own baseline several months before starting the various medication, allowed the team to set realistic expectations of her capabilities and supported challenging what was perceived by previous teams as the status quo.
With these improvements in cognition, AS was now able to make functional improvements too, carefully scaffolded by TDT interventions to practice skills of daily living.
AS practiced skills such as cooking, shopping and cleaning, all skills which she had prior to admission, but which were lost as a result of prolonged hospital admission.
The description of AS’s case also demonstrates the potential usefulness of repeated cognitive assessment as a further means of monitoring side effects of medications initiated by non-ABI specialists.
In this case, because there had been integrated care and a TDT approach, changes in cognition were correctly assessed as being attributable to changes in her medication regime, rather than a legacy of TBI. In AS’s case, this allowed the clinical team to take steps to address reversible causes of her presentation.
After 6 months, AS had made sufficient progress in her rehabilitation and was able to return home to live independently with support of her personal assistant; without the specialist intervention, she would have required a move into long term residential care.
Plans for ongoing medication monitoring were shared with her general practitioner and her community team.
From a medical stance this case also highlights the importance of routine monitoring of prolactin to enable clinicians to better understand the impact that antipsychotic medication and mood stabilisation medication can have on cognitive function.
Through this case, it can be seen how change in cognitive function resulting from ABI are adversely affected by antipsychotic medications and given the deficits this created for AS without a highly specialist team to explore a holistic view of her needs and TDT working to address functional as well as cognitive, physical and behavioural needs her prognosis for rehabilitation may have been much poorer.
AS practiced skills such as cooking, shopping and cleaning, all skills which she had prior to admission, but which were lost as a result of prolonged hospital admission.
AS practiced skills such as cooking, shopping and cleaning, all skills which she had prior to admission, but which were lost as a result of prolonged hospital admission.
AS practiced skills such as cooking, shopping and cleaning, all skills which she had prior to admission, but which were lost as a result of prolonged hospital admission.
AS practiced skills such as cooking, shopping and cleaning, all skills which she had prior to admission, but which were lost as a result of prolonged hospital admission.
AS practiced skills such as cooking, shopping and cleaning, all skills which she had prior to admission, but which were lost as a result of prolonged hospital admission.
AS practiced skills such as cooking, shopping and cleaning, all skills which she had prior to admission, but which were lost as a result of prolonged hospital admission.
References
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Bostwick, J.R., Guthrie, S.K. and Ellingrod, V.L. (2009). Antipsychotic-Induced Hyperprolactinemia. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 29: 64-73.
Boustani M, Campbell N, Munger S, Maidment I, Fox C. (2008). Impact of Anticholinergics on the Ageing Brain; a review and practical application. Ageing Health 4, 3; 311-320
Fox C, Richardson K, Maidment I, Savva G, Matthews F, Smithard D, Coulton S, Katona C, Boustani M, Brayne C. (2011)Anticholinergic Medication Use and Cognitive Impairment in the Older Population; The Medical Research Council Cognitive Function and Ageing Study. Journal of the American Geriatric Society 59;1477-1483
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Montalvo I, Gutiérrez-Zotes A, Creus M, Monseny R, Ortega L, Franch J, et al. (2014). Increased Prolactin Levels Are Associated with Impaired Processing Speed in Subjects with Early Psychosis. PLoS ONE 9(2): e89428.
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Serri, O. et al (2003). Diagnosis and management of hyperprolactinemia. CMAJ: 169: 575 -757.
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Yao S, Song J, Gao J, Lin P, Yang M, Zahid KR, Yan Y, Cao C, Ma P, Zhang H, Li Z, Huang C, Ding H and Xu G (2018).Cognitive Function and Serum Hormone Levels Are Associated with Gray Matter Volume Decline in Female Patients with Prolactinomas. Front. Neurol. 8:742. doi: 10.3389/fneur.2017.00742
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