Metabolic Syndrome using Second-Generation Antipsychotics: Switching from Second - to Third-Generation Antipsychotics

Woman affected by schizoaffective disorder being treated with Olanzapine 24 developed metabolic syndrome. For this reason, a switch to Aripiprazole, a 25 third-generation antipsychotic, was proposed, resulting in improvements in 26 metabolic parameters, quality of life, and subjective well-being.

PATIENT PROFILE

66-year-old divorced woman, lives alone. Divorced at age 32, has a 25-year-old daughter who provided medical history. Educational and social functioning are poor; she is described as withdrawn and isolated, having completed middle school with low academic motivation. Currently unemployed, she performs light housework for acquaintances and receives 80% disability benefits from INPS.

LIFE EVENTS

Significant events include a highly conflictual marital separation and relocation far from her family of origin.

Regarding the past medical history: nothing relevant. Familial history of obesity, NIDDM, and AMI.

PSYCHIATRIC HISTORY

Psychiatric onset at 29 with hospitalization in a psychiatric ward, discharged with a diagnosis of paranoid reaction, characterized by persecutory delusions involving her husband, psychomotor agitation, and total insomnia. She believed her husband intended to kill her to be with his mistress—she stopped eating at home, spent time hiding, and obsessively monitored him with calls. These behaviors persisted chronically, albeit with fluctuations.

Post-discharge, she consulted various private psychiatrists and took several antipsychotics inconsistently: Haloperidol, Fluphenazine, Clotiapine, Risperidone, Olanzapine, with generally good tolerability. Brief depressive phase during her divorce treated with Paroxetine and Trazodone. At 32, she was involuntarily hospitalized (TSO), then transferred to a private facility accredited by the national health system.

Discharged with a diagnosis of “Acute psychotic decompensation in bipolar schizoaffective disorder (DSM-IV-TR).” Upon discharge, she disengaged from her healthcare providers and discontinued therapy.

First contact with the Forlì Mental Health Center (CSM) was in 2000 (age 48), brought by police after disputes with neighbors. She presented marked agitation, bizarre behavior, supernatural beliefs, telepathy, persecutory delusions, complex auditory hallucinations.

Quote: “I was just defending myself; the neighbor is tormenting me with noise and is conspiring with the others to get rid of me.”

Prescribed:

• Haloperidol 4 mg/day
• Valproate (Depakin Chrono) 800 mg/day
• Delorazepam 2 mg/day
• After a month: significant improvement.

Diagnosis: Acute psychotic decompensation in Bipolar Type Schizoaffective Disorder (DSM-IV-TR).

She discontinued treatment upon discharge Due to the onset of side effects such as and akathisia, and the persistence of complex auditory dysperceptions and persecutory delusional ideation, grandiosity and busyness, loosening of associative connections, imaginary disorganization, and global insomnia, Olanzapine titrated to 20 mg/day is prescribed, taken regularly thanks to the administration by the daughter.

Over time, persistent delusions, grandiosity, disorganized thinking, insomnia, with consistent Olanzapine 20 mg/day administered by her daughter.

Psychometric testing:

• BPRS: Score 45, elevated in disorganization, grandiosity, hostility, suspiciousness, hallucinations, uncooperativeness.
• WHOQOL-BREF: 80/130, deficits in health perception and social relationships.

ANTHROPOMETRIC EVALUATION

• Weight: 110 kg
• Height: 160 cm
• Waist circumference: 132 cm
• BMI: 42.9 – Severe Obesity
• Referred for nutritional counseling, diagnosed with morbid obesity (Grade 3).

WEIGHT HISTORY

Weight increased progressively since menopause (age 50), peaking at 114 kg in 2016. Slight loss followed due to orthopedic surgery needs. Dietary assessment revealed binge eating, especially sweets like cream puffs, in the afternoon and evening. Attempted a personalized low-calorie (1200 kcal) diet but abandoned it. A gastric balloon procedure was recommended.

Physical Activity: None, due to mobility issues.

No smoking or substance abuse.

BLOODWORK

• HbA1C: 53 mmol/mol (NV: 20-42 mmol/mol) (↑)
• Fasting glucose: 138 mg/dl (NV: 60-100 mg/dl) (↑)
• Triglycerides: 250 mg/dl (NV: < 150 mg/dl) (↑)
• Cholesterol: 289 mg/dl (NV: < 200 mg/dl) (↑)
• LDL: 194 mg/dl (NV: < 115 mg/dl) (↑)
• HDL: 45 mg/dl (NV: > 40 mg/dl) (↓)
• Uric acid: 7.4 mg/dl (NV: 3.4 – 7 mg/dl) (↑)
• Fibrinogen: 491 mg/dl (NV: 145-500 mg/dl) (↑)
• TSH: Normal
• Vitamin D: 9 μg/L (↓)

Diagnosis: Metabolic Syndrome – meets all 5 criteria (ATP III/IDF), with high cardiovascular risk due to abdominal obesity and family history.

FURTHER INVESTIGATIONS

• Carotid ultrasound: bilateral wall thickening, 40-50% stenosis at right carotid bifurcation.
• Abdominal ultrasound: mild hepatomegaly with steatosis.
• ECG: Normal (QTc 410 msec)
• Brain MRI: White matter hyperintensities indicating vascular gliosis.

OTHER COMORBIDITIES

• Hypothyroidism (treated with Eutirox 125 μg/day)
• Obstructive Sleep Apnea Syndrome (on CPAP therapy)
• Osteoarthritis (hip replacement pending, on Palexia and NSAIDs)
• Fibromyalgia, Irritable Bowel Syndrome, Tension Headache, Migraine with aura

Pain is variable and stress-dependent: burning, stiffness, contraction, or tension.

THERAPEUTIC SWITCH

Weight gain and metabolic syndrome are the two main clinical reasons for switching antipsychotics (Weiden PJ et al, 2007)

Given her metabolic profile, Olanzapine was replaced with Aripiprazole, per meta-analyses (Bak 2014, Leucht 2017), which showed all antipsychotics cause weight gain except Aripiprazole and Ziprasidone. In this case we chose aripiprazole because it was the newer option available

Aripiprazole is an atypical antipsychotic (third generation) with a pharmacological profile distinct from other available antipsychotics; its efficacy in the treatment of psychotic symptoms is thought to be mediated by the combination of partial agonist activity at dopamine D2 and serotonin 5 receptors and antagonist activity at serotonin 5-HT2A receptors (Otsuka Pharmaceutical Europe Ltd. Summary of product characteristics, 2012)

MECHANISM OF ANTIPSYCHOTIC-INDUCED WEIGHT GAIN

• D2 limbic antagonism → increased appetite, prolactin release
• H1 antagonism (hypothalamus) → appetite increase, sedation
• M3 antagonism → glucose intolerance
• 5HT2C antagonism → hypothalamic neuropeptide Y release, leptin resistance

ARIPIPRAZOLE’S FAVORABLE PROFILE

• Partial D2 and 5HT1A agonist
• 5HT2A antagonist
• No H1 antagonism

SWITCH PROTOCOL

We started a cross tapering switch to aripiprazole which involves gradually decreasing the olanzapine dose while simultaneously increasing the aripiprazole dose over a period of several weeks.

We followed the scheme suggested by Fagiolini (Fagiolini A. et al. 2015 ) We started Aripiprazole with a dose of 10 mg/day for 5 days, followed by an increase to 15 mg/day for an additional 5 days. After two weeks we started reducing Olanzapine at 15 mg/day. After 3 weeks, the available range for aripiprazole was 20 mg/day, and olanzapine was 10 mg/day. After 4 weeks, aripiprazole was 30 mg/day and Olanzapine was 5 mg/day stopped after another week.

• Aripiprazole started at 10 mg, increased by 5 mg every 5 days to 30 mg

Gradual taper of Olanzapine by 5 mg every 20 days two weeks after starting therapy with Aripiprazole

• We also added DEPAKIN CHRONO 900 mg/day (VPA: 67 mg/dl NV 60-100)
• After stabilization, switched to Aripiprazole LAI (Abilify Maintena 400 mg)
• Oral Aripiprazole 20 mg/day discontinued after 14 days

OUTCOME (9 MONTHS LATER)

After 9 months, the patient appears stable with good compensation, complaining of marked daytime sleepiness with limitations in daily activities and consequent demoralization; therefore, it is being considered to reduce Depakine Chrono to 500 mg/day until completely discontinued. She has not developed acute psychotic decompensation, has maintained good mood stabilization without requiring emergency visits or psychiatric hospitalization, and has maintained a low level of awareness of her illness. She has struggled to adhere to nutritional recommendations, has resolved her binge eating, and has undergone regular therapeutic diet checks with a nutritionist and regular blood tests and ECGs within normal limits. She has achieved a weight loss of 12 kg in 11 months (10.9%) with a BMI of 38.2: Obesity 2 and a reduction of three dress sizes.

• Clinically stable, no psychotic relapses or hospitalizations
• Persistent daytime sleepiness, leading to gradual discontinuation of Valproate
• Compulsive eating resolved, 12 kg weight loss (10.9%), BMI reduced to 38.2
• Improved metabolic parameters, although still outside the normal reference values :
• HbA1C: 47 mmol/mol (NV: 20-42 mmol/mol) (↓)
• Glucose: 122 mg/dl (NV: 60-100 mg/dl) (↓)
• Triglycerides: 180 (NV: < 150 mg/dl) (↓)
• Cholesterol: 202 mg/dl (NV: < 200 mg/dl) (↓)
• Uric Acid: 5.2 mg/dl (NV: 3.4 – 7 mg/dl) (↓)
• Fibrinogen: 396 mg/dl (NV: 145-500 mg/dl) (↓)
• TSH, CPK, PRL, Elettrolities normal values

PSYCHOMETRIC IMPROVEMENT

• BPRS: from 45 to 26
• WHOQOL-BREF: from 80 to 96/130Notable gains in physical and social domains

These findings align with existing literature (Kane 2012, Fleischhacker 2014, Morosini 2000).

The metabolic and psychopathological condition remained stable for a further twelve months

DISCUSSION

In this single case, we obtained good results switching olanzapine to aripiprazole, but we cannot clearly draw definitive and generalizable conclusions. The case described has significant limitations related to the presence of other variables that may have contributed to achieving weight loss, such as the suspension of valproic acid and increased physical activity. Furthermore, there may be a selection bias in the patient, who, being mild, showed high levels of cooperation.

Another interesting result is related to the finding of the REDUCTION OF somatic PAIN, with fewer migraine attacks and intensity, and a reduction in widespread muscle and joint pain. This led to the use of NSAIDs as needed and a reduction in the Palexia dosage from 100 mg/day to 50 mg/day. The reduction in subjective pain could be due to weight loss, improvement in clinical symptoms, normalization of metabolic parameters, and the use of Aripiprazole.

As noted by Yunus (2007), conditions like fibromyalgia, migraine, IBS, and tension headaches fall under Central Sensitivity Syndromes caused by central sensitization, involving hyperexcitable neurons and altered neurotransmission.

Studies (Fei 2015, Santos 2015) suggest Aripiprazole has antinociceptive effects, both centrally and peripherally, through:

• Partial D2 agonism (nigrostriatal and spinal)
• 5HT1A partial agonism (peripheral)
• D3 antagonism (mesolimbic)
• Raising psychological pain threshold

It would be interesting to further investigate this interesting aspect related to the action of aripiprazole in this population.

CONCLUSIONS

Monotherapy with Aripiprazole made it possible to maintain good clinical stabilization, preventing relapses and psychiatric hospitalizations. It promoted weight loss and enabled the patient to undergo hip replacement surgery, improved metabolic parameters, enhanced overall health, and positively impacted the patient’s subjective perception of quality of life in both physical and social domains. Finally, it contributed to a reduction in pain perception, allowing for decreased use of centrally acting painkillers and NSAID.

Conflict of interest statement

The authors declare no conflict of interest.

Funding

None.

Authors contribution

Study design: M.P. Data collection: all authors. Critical revision of the manuscript: M.P. Approval revision of the manuscript for pubblication: all authors

Ethical consideration

Authors removed all identifying details, including dates, locations, and initials. It is impossibile to recognize the person involved.