Sodium-oxybate as a potential new treatment for catatonia in patients with depression, bipolar disorder or a psychotic disorder, a randomized controlled trial. The Laborit study.

Rationale: Catatonia is a severe syndrome in patients with depressive-,
bipolar- and psychotic disorders. Untreated catatonia has a mortality of 10%
and results in increased morbidity; renal failure, rhabdomyolysis, pneumonia,
embolism and contractures. Novel therapies are needed for patients with
catatonia. Currently, the only pharmacological treatment option for catatonia
consists of high dose of lorazepam, a benzodiazepine and gamma-aminobutyric
acid (GABA)-A receptor agonist. When lorazepam fails (in 25% of the patients),
the only remaining treatment is electroconvulsive therapy (ECT). Many patients
and their caregivers are reluctant to receive ECT, because of its *intrusive*
nature and because of its cognitive side effects. However, most accept ECT
because currently no other treatment is available.
ECT is probably successful in catatonia because it causes a huge increase in
GABA levels and GABA-B function2. This has raised the question whether
alternative routes of GABAergic modulation represent a novel treatment option.
One observational study showed efficacy of sodium oxybate in patients with
catatonia. We hypothesize that sodium oxybate is an alternative to ECT, since
it is a precursor of GABA and acts as GABA-B receptor agonist. Such a
pharmacodynamic profile is expected to increase GABA mediated neurotransmission
levels in the brain, and is thus beneficial to patients with catatonia.

Hypothesis: Is sodium oxybate effective in psychiatric patients with catatonia,
admitted to an acute psychiatric ward, who are resistant to prior treatment
with lorazepam?

This study has been transitioned to CTIS with ID 2024-517805-10-01 check the CTIS register for the current data.

We aim to investigate whether sodium oxybate can be used as a novel treatment
in psychiatric patients with catatonia.
Our primary objective is: To determine if sodium oxybate is effective as a
novel treatment in psychiatric patients with catatonia who are resistant to
lorazepam, in a randomized controlled trial. This is obtained by comparing
response to either high dose of lorazepam or sodium oxybate, after 4 days of
treatment.
Our secondary objectives are:
1) To determine remission of catatonia, by comparing remission to either high
dose of lorazepam or sodium oxybate, after 10 days of treatment. 2) To
determine which side effects occur if sodium oxybate is administered in
patients with catatonia, with an emphasis on oxygen levels, blood pressure,
heart rate and vomiting, i.e. with regard to the risk to develop aspiration
pneumonia.

The Laborit study combines a multicenter, prospective cohort study on patients
with catatonia, admitted to a psychiatric hospital with an embedded randomized,
controlled superiority trial to examine the effect of sodium oxybate on
catatonia.
1) Patients with catatonia will receive care as usual: they will be titrated to
a high dosage of lorazepam in 4 days, until response of catatonia symptoms
occurs.
2) If no response occurs, patients will be randomized between continuation of
high dose of lorazepam (n=21) for an additional 4 days or sodium oxybate (n=21)
for 4 days.

The cohort provides the basis for recruitment of patients for the RCT, since in
patients with catatonia there is only a limited timeframe to determine whether
the next and final step (ECT) in the treatment protocol should be taken. The
timeframe to decide is limited since the morbidity and mortality of catatonia
is high. The cohort additionally provides an excellent opportunity to describe
clinical characteristics and course of patients with catatonia and identify
putative determinants.

1) Patients with catatonia will receive care as usual: they will be titrated to
a dosage of lorazepam up to 24mg daily in 4 days, until response of catatonia
symptoms occurs.
2) If no response occurs, patients will be randomized between continuation of
high dose of lorazepam (n=21) for an additional 4 days or sodium oxybate (n=21)
for 4 days.

Benefits: Novel treatments for catatonia are necessary, since currently there
are only two options, first administration of high dose lorazepam, during 4
days to 7 days and 2) if this fails ECT. This study could -if successful-
contribute to a less invasive treatment with sodium oxybate in patients with
catatonia who do not respond to lorazepam.
On a participant level, there might be a potential beneficial effect in those
allocated to sodium oxybate.
Burden: Total time for participants ranges between 4 and 10 days. 4 days for
those who do not respond to treatment and 10 days for those who do respond to
treatment with sodium oxybate.
Risk: Sodium oxybate can produce deep sedation, nausea and dizziness4.
Overdosage can result in respiratory depression. Co-administration with
benzodiazepines increases risk for impaired consciousness and respiratory
depression. Safety is of the utmost importance for this study, therefore
patients will be monitored continuously when they start sodium oxybate for the
first four days. Anaesthesia technicians, capable of treating respiratory
depression, having access to oxygen and a crash cart and able to intubate
patients, will be assigned to observe the patients continuously. Apart from
these anaesthesia technicians, patients will receive normal care from
psychiatric nurses at the psychiatric wards.