Digital archive of theses discussed at the University of Pisa


Thesis etd-10202022-182346

Thesis type
Tesi di specializzazione (4 anni)
Thesis title
Mood stabilizers impact on circadian rhythms in patients with bipolar disorder in euthymic phase
Course of study
relatore Prof.ssa Carmassi, Claudia
  • bipolar disorder
  • lithium
  • mood stabilizers
  • circadian rhythms
Graduation session start date
Release date
Bipolar Disorder (BD) is one of the most severe psychiatric illnesses. Its impact on quality of life and global functioning can be very high, determining marked impairment. BD is often associated with circadian rhythm disruption with prevalent evening preference, even during intervals between episodes. All biological process across 24h, such as body temperature, hormone secretion, sleep-wake cycle, are determined and regulated by circadian rhythm, and any biological rhythm can be measured with many techniques among which actigraphy, chronotype evaluated with questionnaires can be considered. Actigraphy, measured by a sensor worn on non-dominant wrist, has demonstrated that subjects with BD have less stable and more variable circadian rest-activity rhythm. The analysis of chronotype, the behavioural manifestation of circadian rhythms, also known as Morningness-Eveningness can be evaluated with specific questionnaires.
Lithium is one of the most widely used drugs in BD; its extraordinary value is due to his efficacy in reducing recurrence, suicide, and mortality risk. Unfortunately, only about 30% of patients treated with lithium obtain a clinical complete remission, and there are no known factors that can help in predicting individual response. The increasing knowledge about the role of lithium in regulating circadian rhythms, the impact of circadian disruption on BD and the association of circadian abnormalities in euthymia and relapses, could be useful in developing strategies to prevent recurrences in BD.
64 patients with diagnosis of BD according to DSM-5 criteria, in euthymic phase (Hamilton Depression Rating Scale [HDRS] < 7/ Young Mania Rating Scale [YMRS] <6), aged between 18 and 65, with high school studies and able to sign an informed consent, without a history of neurological disease were selected among outpatients at Psychiatric Unit. They have been evaluated by actigraphy determining sleep variables (Total Sleep Time (TST), Sleep Latency (SL), Wake After Sleep Onset (WASO), Sleep Efficiency (SE), Sleep Onset Time) and circadian variables (acrophase, mesor, amplitude, inter-daily variability and intra-daily stability, sleep regularity index); then they were evaluated with questionnaires to evaluate chronotype (Morningness-Eveningness Questionnaire-MEQ), perceived sleep quality (Pittsburgh Sleep Quality Index-PSQI), and cognitive test (Psychomotor Vigilant Test-PVT), and collecting data about prescribed drugs. A group of healthy subjects (n=100) was collected as healthy control group.

64 patients with BD in euthymia were divided into two groups: 34 treated with lithium with or without other mood stabilizers (BD_LI+OMS) and 30 treated only with other mood stabilizers (BD_OMS). They were compared with 100 healty controls (HC). Significant differences were found between the three groups (HC vs BD_LI vs BD_OMS) in cigarettes intake, BMI, rMEQ, PSQI, Actigraphic SE, WASO, TST, Interdaily stability and PVT lapses. Significant differences between HC and BD_OMS were found in actigraphic SE (p-value = 0.009), WASO (p-value = 0.001), TST (p-value = 0.002). Significant differences between HC and BD_LI were found in Interdaily stability (IS) (p-value = 0.03), having lower IS the group of BD_LI compared to controls, while no differences in IS were found between BD_OMS and HC. Regression models with cognitive and sleep/circadian variables as outcomes and Clinical Group (BD+LI vs BD+OMS) as predictor adjusting for potentially confounding factors (Age, sex, years of education, BMI and clinical variables = number of admissions and years of disease duration) showed that the BD_OMS group showed lower sleep efficiency (β= -7.57, p-value = 0.004), higher WASO (β= 42.38, p-value = <0.001) increased TST (β= 1.35, p-value = 0.008) and higher scores in the PSQI (β= 4.45, p-value = 0.001) compared to the BD_LI & LI+OMS group.

Patients affected by Bipolar Disorder (BD), even in euthymic phase, show strong alterations in lifestyle, particularly in sleep quality and chronotype.
BD patients not treated with lithium show worse sleep efficiency, more waking even after sleep onset, and increased total sleep time compared to those treated with lithium.
Perceived sleep analysis trough self-report questionnaire (PSQI) shows that both groups feel a worse sleep quality than healthy controls.
Lithium seems to be a potential predictor for disease course severity, given that patients treated with lithium show a larger number of hospitalizations.