Foreword: the recommendations proposed concerning the use of drugs are dependent on the prescribing information in the current SPC (Summaries of Product Characteristics) or the legal information regarding the products quoted. This prescribing information is established by the ANSM (French Drugs and Healthcare Administration), recent publications, or prescription databases. These publications describe the contra-indications, precautions and conditions of use, adverse effects, clinical or paraclinical monitoring to be organised and recommendations to be adopted. Only specificities linked to populations after a traumatic brain injury are considered here.
The literature review explored evidence in favour of using beta-blockers, antipsychotic drugs, anticonvulsant mood stabilizers, antidepressants, benzodiazepines, amantadine, and other molecules for treating the behavioural disorders defined in question 1.
4.1. Beta-blockers
The mechanism of action of beta-blockers on behavioural disorders is unclear.
Observation: In some cases, beta-blockers, and in particular propranolol, help improve aggressiveness after a traumatic brain injury.
R56: The marketing authorisation (MA) for beta-blockers does not include the treatment of agitation and/or aggressiveness and/or irritability. However, the literature review shows that in some cases they can improve these symptoms. Their prescription for this indication must be assessed case by case according to criteria associated with off-label treatments in addition to precautions of use linked to this therapeutic category. A dose of 40 to 80 mg per day of propranolol is proposed to treat agitation and/or aggressiveness and/or irritability, even if some studies have shown effects with higher doses. It is advisable, as in non-TBI patients, to begin treatment progressively. It is also essential to stop beta-blockers progressively due to the coronary risk. It is advised to perform an ECG before starting treatment with beta-blockers (EC).
4.2. Neuroleptic and antipsychotic drugs
Observation: There is not enough proof regarding the efficacy of neuroleptic drugs for the treatment of behaviour disorders such as irritability, aggressiveness or apathy in patients with severe traumatic brain injuries.
Observation: There are no "new" or specific adverse effects linked to the use of neuroleptic drugs after a traumatic brain injury. There are however several particularities that must be considered: (i) greater exposure to neuroleptic malignant syndrome; (ii) sedative effect that can increase the risk of swallowing the wrong way; (iii) potentially deleterious effects on brain plasticity and therefore recovery potential.
R57: In an emergency or during an acute episode of agitation and aggression, prescribing a neuroleptic drug can be considered, in the absence of contra-indications, to achieve rapid sedation to protect the patient from themselves, their close relations or the healthcare team.
The MA for the injectable form of loxapine (LOXAPAC*) includes the treatment of "states of agitation, aggression, and anxiety associated with psychological disorders or some
personality disorders" (EC).
R58: The long-term use of neuroleptic drugs to treat behavioural disorders in TBI patients must be avoided due to adverse effects, except in the case of a prior psychiatric illness (EC).
R59: When no therapeutic alternative is available, the use of neuroleptic drugs must comply with the general rules for prescribing this therapeutic category. Moreover, in traumatic brain injury patients, common prescribing rules for the various therapeutic agents are
recommended (cf. question 5). Additional precautions need to be taken regarding antipsychotic drugs (EC):
· take into account the epileptogenic risk of which the threshold can be lowered,
· privilege the use of atypical neuroleptic drugs (2nd generation) as they induce less adverse effects and in particular less extrapyramidal symptoms,
· take into account the cardiovascular risk.
4.3. Anticonvulsant mood stabilizers and other anticonvulsants
The Vidal indications for carbamazepine include the prevention of relapses within the context of bipolar disorders, in particular in patients with relative resistance, contra-indications, or lithium intolerance, and for the treatment of manic or hypomanic states of excitation.
Concerning divalproate, the Vidal notice reports the treatment of manic episodes of bipolar disorders in the case of contra-indications or lithium intolerance. The continuation of the treatment following a manic episode can be envisaged in patients who responded to sodium divalproate during an acute episode.
Observation: The use of anticonvulsants for the curative or prophylactic treatment of epilepsy in TBI patients suggests that carbamazepine and divalproate or sodium divalproate may be effective in treating agitation and aggressiveness.
R60: Carbamazepine (CBZ) (TEGRETOL®) and sodium valproate (VPA) (DEPAKINE®) are recommended as a first line treatment of agitation, aggressiveness, anger, and irritability in traumatic brain injury patients, notably when there is mood lability. Nevertheless, the treatment of agitation, aggressiveness, anger and irritability is beyond the MA of mood stabilizing anticonvulsants, and prescribing these molecules must be evaluated case by case according to the criteria associated with treatments prescribed beyond MA in addition to the precautions of use (EC).
Observation: Sodium divalproate is described to act rapidly with a relatively standardized dose of 1250 mg.
Observation: The efficacy of carbamazepine is reported to be good with a dose of 400 to 900 mg/day and no negative cognitive effect.
Observation: Carbamazepine has been reported to improve the Klüver-Bucy post-traumatic syndrome.
Observation: Some authors prefer oxcarbazepine (OXC) (TRILEPTAL®) to CBZ due to its efficacy on agitation and aggressiveness, and better adverse effects profile.
Observation: Improvement in aggressiveness and spasmodic laughing and crying has been reported in case studies with Lamotrigine (LAMICTAL®).
Observation: Levetiracetam (KEPPRA®) has no beneficial effect on aggressiveness after a traumatic brain injury.
R61: Levetiracetam (KEPPRA®) must be avoided after a traumatic brain injury due to the risks of behavioural disorders and mood disorders induced by the product (EC).
4.4. Antidepressants
R62: The primary indication of antidepressants is to treat depression in accordance with the standard recommendations and the MA. In the absence of counterargument, they can be used in traumatic brain injury patients (EC).
R63: Antidepressants for treating depression throughout the progression must be prescribed according to the recommendations for clinical practice published by the ANAES in 2002:
"treatment of isolated depressive episodes in adult outpatients" (EC).
R64: It is specified in particular that the choice of an antidepressant be based predominantly
on a few specific criteria (Grade C):
- therapeutic use of side effects (for example, to produce sedation, anxiolysis, or stimulation);
- preferential indication of a therapeutic category in certain psychiatric co-morbidities, for example SSRI (Selective Serotonin Reuptake Inhibitors) and in particular sertraline for obsessive compulsive disorders;
- combined effect SSRI + adrenergic (SNRI) on cognitive disorders: for example 30 to 150 mg of milnacipran (IXEL®).
Observation: Antidepressants could have an indirect effect on agitation and aggressiveness as depression or anxiety is a contributing factor.
Observation: Amitriptyline has been shown to be effective in the treatment of agitation from 25 mg per day.
Observation: Paroxetine and Citalopram can improve pathological tears in some TBI patients.
Observation: SSRI could have a beneficial effect on brain plasticity and therefore the potential of recovery.
Observation: Doses of up to 200 mg per day of sertraline have been shown to be relatively effective in the treatment of agitation, aggressiveness, and irritability.
Observation: Improvement of Klüver-Bucy syndrome (agitation, hyperorality, hypersexuality) after severe traumatic brain injury has been reported with up to 150 mg/day of sertraline. The beneficial effect was potentiated by combining sertraline with a neuroleptic drug.
R65: In the absence of specific indications, it is recommended to choose an antidepressant that is the best tolerated, the least dangerous in the event of a massive intake, and the easiest to prescribe at effective doses. SSRI, SSNRI (Selective Serotonin and Noradrenalin Reuptake Inhibitors) and other non-tricyclic non-MAOI antidepressants correspond best to these requirements. During waking periods, tricyclic antidepressants, and in particular low dose amitriptyline, can also be proposed to treat agitation (EC).
R66: The MA for antidepressants does not include the treatment of agitation, aggressiveness, anger, and irritability; so, prescribing these molecules must be evaluated case by case according to the criteria associated with treatments prescribed beyond the MA and the precautions of use (EC).
4.5. Benzodiazepines
Observation: There is not sufficient proof regarding the efficacy of benzodiazepines in the treatment of agitation or aggressiveness in traumatic brain injury patients.
R67: BZD can be used during episodes, but must not be used for the long-term treatment of agitation after a traumatic brain injury. Use should be limited to situations where anxiety is the predominant symptom and be short-term (symptomatic prescription) (EC).
R68: In traumatic brain injury patients, the risk of causing or aggravating problems of vigilance, attention and/or memory, causing respiratory depression, inducing a paradoxical effect on agitation, or inhibiting brain plasticity must be taken into consideration when using benzodiazepines (EC).
4.6. Amantadine
Observation: There is not sufficient proof regarding the efficacy of amantadine in the treatment of agitation, aggressiveness, and anxiety in TBI patients.
Observation: Improvement in apathy, taking initiative, or motivation disorders has been reported in case studies with 300 mg per day of amantadine.
R69: The MA for Amantadine does not include the treatment of apathy; so, prescribing this drug must be evaluated case by case according to the criteria associated treatments prescribed beyond the MA and the precautions of use (EC).
4.7. Other molecules
4.7.1. Buspirone (Buspar®)
Buspirone is a serotonergic agent, as well as a combined dopamine agonist/antagonist used for agitation and outbursts of violence in dementia, mental retardation, autism, or brain damaged patients. This non-benzodiazepine treatment has no sedative or addictive effects, or interactions with anticonvulsants or respiratory depressant effect. However, this product is slow acting; the onset of the anxiolytic effect is approximately 2 to 3 weeks and it takes 12 to 36 weeks to improve agitation.
The anxiolytic effect can improve agitation in some patients with anxiety disorders.
R70: In some TBI patients, Buspirone has been seen to improve agitation, aggressiveness, and irritability. Considering the relatively low level of proof, it must not be used as a first line treatment. Controlled studies are necessary (EC).
4.7.2. Hydroxyzine (Atarax®)
Hydroxyzine (Atarax®) can be used as an anxiolytic. The advantage of this treatment is that the respiratory depressant effect is lower than with some benzodiazepines. This drug should not be administered to patients with cognitive disorders or delirium due to the risk of aggravation linked to the product's pharmacodynamic properties.
4.7.3. Use of hormonal agents
According to the Vidal data, medroxyprogesterone (DEPOPROVERA®) is a long-acting contraceptive (3 months) used when other methods of contraception cannot be used. The MA does not include the treatment of sexual disorders.
R71: In certain cases, medroxyprogesterone has decreased hypersexuality-type disorders in TBI patients. Considering the relatively low level of proof and the limited number of studies, it must not be used as a first line treatment. Controlled studies are required to confirm the efficacy of medroxyprogesterone. Additional studies are necessary to evaluate possible links between sexual disorders and endocrine disorders, especially relating to the gonadal axis, which are common in TBI patients. The prescription of medroxyprogesterone falls within the framework of regulations relating to regional resource centres (EC).
5. Question 5: Treatment strategies