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| Year : 2018 | Volume
: 2
| Issue : 2 | Page : 152-157 |
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Depot preparation in schizophrenia: Indian outlook
Mohit Shah1, Disha Parikh2, Sagar Karia2
1 Consultant Psychiatrist, Unlimited Potentialities, Mumbai, Maharashtra, India
2 Department of Psychiatry, LTMMC and GH, Mumbai, Maharashtra, India
| Date of Web Publication | 30-Nov-2018 |
Correspondence Address:
Mohit Shah
603, Aura Biplex Senate, Above Kalyan Jewellers, Borivali West, Mumbai, Maharashtra
India
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/aip.aip_41_18
Schizophrenia is a mostly chronic mental disorder, and symptomatic relapse is frequently observed. It is often associated with social and/or occupational decline that can be difficult to reverse. Most patients with the illness need long-term pharmacological treatment and antipsychotic drugs represent the mainstay of clinical care. Long-acting injectable antipsychotics are an important alternative to oral medication, particularly advantageous in the context of compliance management.
Keywords: Compliance, long-acting injectables, schizophrenia
How to cite this article:
Shah M, Parikh D, Karia S. Depot preparation in schizophrenia: Indian outlook. Ann Indian Psychiatry 2018;2:152-7 |
| Introduction | |  |
Schizophrenia is ”a mental disorder that is characterized by disturbances in thought (such as delusions), perception (such as hallucinations), and behavior (such as disorganized speech or catatonic behavior), loss of emotional responsiveness and extreme apathy, and by noticeable deterioration in the level of functioning in everyday life”. It was not until the 19th century, however, that schizophrenia emerged as a medical condition worthy of study and treatment. Two major figures in psychiatry and neurology who studied the disorder were Emil Kraepelin (1856–1926) and Eugene Bleuler (1857–1939). Earlier, Benedict Morel (1809–1873), a French psychiatrist, had used the term démence précoce to describe deteriorated patients whose illnesses began in adolescence.[1]
In 1887, German Physician, Dr. Emile Kraeplin coined the term ”Dementia Praecox” for individuals who had symptoms that are now associated with schizophrenia. He used this term because his studies focused on young adults with dementia.[2]
Although Kraepelin had some mistaken beliefs about the nature of schizophrenia, he was the first person to distinguish the illness from other forms of psychosis, and in particular from the ”affective psychoses” that occur in mood disorders such as depression and manic-depressive illness (bipolar affective disorder).[3]
Moreover, the bulk of functional deterioration tends to occur in the first 5 years after onset of schizophrenia, after which the illness typically progresses into a stable phase, wherein positive symptoms are decreased and negative, and cognitive symptoms become predominant.[4] Schizophrenia is an illness or a group of illnesses affecting language, planning, emotion, perceptions, and movement.[5]
Schizophrenia is a mostly chronic mental disorder, and symptomatic relapse is frequently observed. It is often associated with social and/or occupational decline that can be difficult to reverse. Most patients with the illness need long-term pharmacological treatment; and antipsychotic drugs represent the mainstay of clinical care. Long-acting injectable antipsychotics (LAIs) are an important alternative to oral medication, particularly advantageous in the context of compliance management.[6]
After a three-decade reign, chlorpromazine and other conventional antipsychotics (APs) such as fluphenazine and haloperidol (with limitations such as selective effectiveness, poor long-term outcomes, and higher risk-to-benefit ratio) were replaced in the early 1980s by clozapine, a second-generation antipsychotic that has minimal or no extrapyramidal side effects. The second generation APs increased tolerability, reduced relapse risk, and improved quality of life.[7]
| Long Acting Injectables | | |
Soon after the introduction of APs in the 1950s, poor adherence to oral formulations was found to be a critical issue. This led to the development in 1966 of the first LAI AP fluphenazine enanthate, and fluphenazine decanoate some 18 months later, to reduce the incidence of side effects of the former. Haloperidol decanoate became available in Europe in 1981 and in the USA in 1986. Clinical trial results showed a dramatic reduction in the morbidity of schizophrenia.
Once steady-state is achieved, plasma levels remain relatively stable, avoiding the daily peaks and troughs that occur with oral agents. In addition, the Local Aggregates Assessment depots facilitate the use of the lowest effective dose principle, thereby reducing the probability of medication overdose and the frequency of adverse events such as akathisia, dysphoria, and antipsychotic-induced deficit syndrome, and thus enhancing the patient's quality of life.[7]
However, the concept of LAIs for schizophrenia was not initially received warmly by the medical profession for fears of increased side effects, lack of efficacy, and the fact this was seen as an attempt by psychiatrists to impose a treatment on patients without due regard to their feelings or rights as well as the potential for medico-legal problems. However, with subsequent surveys and trials suggesting their benefits, LAIs became more widely adopted.[8]
| Compliance in Schizophrenia | | |
It is often seen that subjects with schizophrenia do not keep their appointment for a detailed evaluation after initial evaluation in the walk-in clinic or follow up. Indian studies have reported noncompliance with oral medications in 58% of the patients.[9] Patients place more importance on whether they think medication is efficacious as opposed to other factors, such as side effects. It is therefore important to provide patients with information about the efficacy of a particular medication and to have an honest appraisal process in place to evaluate all treatment options.[10]
| Depot Preparations Available in India | | |
The available first-generation LAI are haloperidol decanoate, flupenthixol decanoate, fluphenazine decanoate, and zuclopenthixol decanoate[11] [Table 1]. | Table 1: First-generation antipsychotics available as long-acting injectable medications
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The efficacy of first-generation LAI is comparable with risperidone LAI (RLAI) and no significant difference was observed in outcomes.[12] The risk of relapse, extrapyramidal symptoms and need for anticholinergic drugs between LAI and oral APs were similar as found in various studies. In patients with a history of violence, zuclopenthixol LAI reduced violent behaviors. First-generation LAI showed lower discontinuation rates and greater mean time to discontinuation for any cause compared with oral APs. Fluphenazine LAI showed lower hospitalization rates when compared with several oral APs. However, more prescriptions for anticholinergic drugs were needed in the first-generation APs (FGA)-LAI group.[13]
Second generation long acting injectables
The various second generation long acting injectables[14] are as follows: [Table 2]. | Table 2: Second-generation antipsychotics available as long-acting injectable medications
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Risperidone long-acting injectables
Indication
RLAI is indicated in the maintenance treatment of schizophrenia in patients on oral APs. RLAI is not recommended for patients below 18 years of age.
Dosage
Before the first injection of RLAI, the patient is recommended to be on oral risperidone no shorter than 2 weeks. RLAI doses are available as: 25, 37.5, and 50 mg. RLAI should be used in the lowest effective dose, usually given every 2 weeks. The administration of RLAI less frequently than every four weeks is not recommended. In the event of discontinuation, it needs to be taken into account that the risperidone level will maintain for at least 3 weeks after the last injection. RLAI dose can be increased every 4 weeks. The maximum RLAI dosage is 50 mg every 2 weeks. In the elderly, the usual RLAI dosage is 25 mg every 2 weeks.
Adverse effects
The most frequently observed side-effects are insomnia, anxiety, headache, upper respiratory tract infections, depression, akathisia, and an increase in prolactin level. In the case of side-effects, it is recommended to consider lowering the RLAI dose and frequency of injections. The use in patients with dementia or with cerebrovascular disorders requires caution. There is a higher risk of morbidity and mortality in these patients.
Drug interactions
The potential drug interactions are with L-dopa and DA-agonists, phenothiazines, tricyclic antidepressants, β-blockers, lithium, valproate, and donepezil.
Olanzapine long-acting injectables
Indication
Olanzapine long-acting injection (OLAIs) has been indicated for the maintenance treatment of adult schizophrenic patients who have been stabilized on oral olanzapine.
Dosage
OLAI is available in three doses: 210, 300 and 405 mg of olanzapine pamoate monohydrate powder and solvent for prolonged-release suspension for injections. The half-life of OLAI is 30 days. When the patient had already been stabilized on oral olanzapine, the OLAI should be given at the lowest possible dosage, usually at the intervals of 4 weeks.
The drug should be administered deeply into the gluteal muscle. The administration of the drug should take place under conditions which allow for observation of patient to look out for postinjection syndrome. For maintenance treatment in schizophrenia usually, the lowest possible dose of OLAI is administered every 4 weeks. The oral dose can be given simultaneously, but the total equivalent dose should not exceed 20 mg.
The dose should be reduced in the presence of factors which can slow down the olanzapine metabolism, such as female gender, older age, and nonsmoking patient.
Adverse effects
The adverse effects for olanzapine use include the risk of body weight gain, and metabolic syndrome, abnormal lipids levels as well as hyperglycemia. This may lead to the development or exacerbation of diabetes, including rare complications such as ketoacidosis and coma. Side-effects at the injection site were seen in about 8% of patients. The most common injection site side-effect was pain in about 5% of patients.
Postinjection syndrome is a rare complication of OLAI treatment which has been noted less frequently (1/1000 OLAI injections). Due to its symptoms: sedation and/or delirium, agitation, anxiety, and cognitive dysfunctions, after every OLAI injection, the patient has to be under the close supervision of medical personnel for three hours. As it produces stable serum levels, the OLAI may be better tolerated in terms of somnolence, fatigue, and orthostatic hypotension than oral olanzapine.
Drug interactions
Its metabolism can be induced by tobacco smoking and carbamazepine taking which may result in lowering olanzapine levels. Fluvoxamine and ciprofloxacin cause a significant inhibition of olanzapine metabolism.
Aripiprazole long-acting injectables
Indications
Aripiprazole long-acting injection (ALAI) is indicated for maintenance treatment of patients with schizophrenia who have been stabilized by oral antipsychotic treatment. ALAI is not indicated for elderly and dementia patients. It is not indicated for patients less than 18 years.
Dosage
Patients who have not been treated with aripiprazole before the initiation of ALAI should at first be treated with aripiprazole administered orally. Those who have already been treated with oral aripiprazole should receive 400 mg of ALAI with the simultaneous continuation of oral aripiprazole for 14 days to assure stable serum aripiprazole levels.
ALAI injections should be given every 4 weeks. In case of intolerance, the dose can be decreased to 300 mg, every 4 weeks. The half-life (T1/2) of ALAI given in a dose of 400 mg is 47 days, and for 300 mg, 30 days.
Adverse effects
The most common ALAI side-effects are insomnia, akathisia, and body mass change. About 7.5% patients who received 400 mg of ALAI a pain of moderate severity was observed at the injection site.
Drug interactions
Aripiprazole is metabolized with the use of isoenzymes 3A4 and 2D6 of the cytochrome P450. Potential drug interactions are with carbamazepine and ketoconazole.
Paliperidone long-acting injectables
Indications
It is indicated in schizophrenia patients after at least one relapse or exacerbation of symptoms in the patient's history caused by the persistent lack of adherence to treatment, who respond to treatment with risperidone and paliperidone. PLAI should be used in patients who have been stabilized under risperidone or paliperidone treatment. In selected patients who have previously shown a favorable response to oral paliperidone or risperidone, PLAI can be used without the previous stabilization of patients with oral antipsychotic treatment. PLAI should not be used for patients with acute psychoses and/or those who require immediate sedation. The use of PLAI in the population of elderly patients has not been studied.
Dosage
PLAI is available in the doses of (suspension for injection with prolonged release) 25, 50, 75, 100, and 150 mg. The initiation of treatment is recommended with the 150 mg dose and after a week (8 days after the first injection) a dose of 100 mg should be given. Both injections should be given into the deltoid muscle to reach the therapeutic serum level of paliperidone as quickly as possible. The recommended maintenance dose is 75 mg monthly; in the range from 25 to 150 mg, depending on individual tolerability and efficacy. Obese or overweight patients may require higher doses. Adjustment of the treatment dose may be done in monthly intervals. In the case of discontinuation of PLAI treatment, the prolonged phenomenon of paliperidone release should be considered.
Adverse effects
The following side-effects have been observed: insomnia, headache, body weight increase, injection site reactions, agitation, somnolence, akathisia (dose-dependent), nausea, constipation, dizziness, tremor, vomiting, orthostatic hypotension, diarrhea, and tachycardia. Caution should be given to patients who suffer from cardiovascular diseases or have prolonged QTc or have disturbances of cerebral circulation. The risk of tardive dyskinesia should be considered. In the case that the symptoms of tardive dyskinesia are present, the discontinuation of the antipsychotic drug should be considered. Paliperidone should be administered with caution to patients with elevated prolactin levels during treatment. The drug should not be given in patients with moderate to severe renal conditions or with serious liver failure.
Drug interactions
Significant drug–drug interactions of PLAI are with drugs that may prolong the QTc interval, for instance with antiarrhythmic drugs such as disopyramide, amiodarone, or sotalol, as well as with some antihistaminic drugs and carbamazepine.
There are few newer depot preparations which are not available currently in India[11] [Table 3].
Oral Depot
Penfluridol is an unusual long-acting oral antipsychotic agent for the treatment of schizophrenia. It has the unusual property of lipophilicity and distributes extensively in fatty tissues following oral administration. This depot effect produces a very slow release of drug from the tissues and results in a very long duration of activity. The oral doses of 20–100 mg/week are considered efficacious.[15]
The efficacy and adverse effects profile of penfluridol are similar to other typical APs; both oral and depot. Furthermore, penfluridol is shown to be an adequate treatment option for people with schizophrenia, especially those who do not respond to oral medication on a daily basis and do not adapt well to depot drugs. One of the results favoring penfluridol was a lower dropout rate in medium term when compared to depot medications. It is also an option for chronic schizophrenia patients with residual psychotic symptoms who nevertheless need continuous use of antipsychotic medication. An additional benefit of penfluridol is that it is a low-cost intervention.[16]
| Advantages of Depot Preparations | | |
The advantages of using depot preparations are as follows[8]:
- Early identification of nonadherence
- Eliminates bioavailability problems
- Providing a mechanism for monitoring adherence with injections
- No need to remember to take medication every day
- Regular interactions between patient and medical staff
- Reduced relapse frequency and rehospitalization rates
- Reduces risk of an overdose of medications in suicidal intention
- Clear attribution of the cause of relapse or nonresponse, discriminating between nonadherence or lack of response
- Treating patients with more stable plasma concentrations than oral medications
- Structured management of the patient, his/her illness and his/her treatment far beyond the simple administration of a drug
- Avoidance of first-pass metabolism-better relationship between dose and blood level of drug
- Lower and less frequent peak plasma level-reduced side effects
- In many low- and middle-income countries, continuous availability of antipsychotic medicines in nonspecialized health care is a challenge; therefore, depot preparations may have the advantage of requiring a smaller quantity of medications per year
- Depot formulation can be beneficial for treatment adherence in settings where there is low human resource availability to provide continued care through follow-up or where access to care is difficult. In many countries, per day cost may be reduced with the use of depot preparations.
| Disadvantages of Depot Preparations | | |
The disadvantages of using depot preparations are as shown below[8]:
- Slow-dose titration
- Longer time to achieve steady-state levels
- Less flexibility of dose adjustment
- Delayed disappearance of distressing and/or severe side effects
- Pain at the injection site can occur, and leakage into the subcutaneous tissue and/or the skin may cause irritations or lesions (especially for oily LAI)
- The burden of frequent travel to outpatient clinics or home visits by community nurses for their administration
- RLAI needs refrigeration, which may be cumbersome in some latitudes
- Perception of stigma
- In some countries, the cost of second-generation depot preparations is much higher, which may preclude their use
- In many countries, the availability of health-care staff needed to administer an injection may be a significant barrier to delivering these interventions
- The use of depot preparations requires the patient and families to return to the health care facility at regular intervals, facilitating psychosocial interventions.
| Practical Points | | |
The following practical guidelines should be ensured while using depot preparations[17]:
- Ensure the needle is of adequate length (a minimum of 1.5 inches is recommended)
- Sterilize the skin before injection
- Z-tracking technique: using the thumb, apply a shearing stress to the skin so that the skin and subcutaneous tissue slide over the underlying muscle. Inject through the displaced skin with a smooth action
- If resistance is felt, it probably indicates contact with the ilium and the needle should be withdrawn ½ ”to 1” before depressing the plunger
- As with all oily injections, it is important to ensure, by aspiration before injection, that inadvertent intravascular injection does not occur
- Injections should be alternated between the two sides and never be given thorough the same puncture hole as a previous injection
- For second-generation depot, patients tolerability, and safety to oral preparation of same APs should be established
- Risperidone depot requires cold chain.
| Personal Experience | | |
We have found depot preparation to be very useful in the management of schizophrenia. Several admitted patients of schizophrenia are started on depot preparations before discharge from the hospital.
The choice of depot depends on tolerability, side effects, cost, and patient's profile.
First-generation depots are very reasonable and effective.
Second-generation depots are better tolerated than first generation but cost can be a limiting factor.
There are few differences between individual FGA LAIs.
With the exception of zuclopenthixol, these preparations are equally effective with respect to each other. Zuclopenthixol depot may be more effective in preventing relapses than others, although this may be at the expense of an increased burden of adverse effects. Fluphenazine depot is more effective in chronic schizophrenia. Haloperidol depot is more effective for controlling hostility and aggression. Flupenthixol depot is more effective in reducing negative symptoms.
Paliperidone, risperidone, and olanzapine LAIs have a relatively lower propensity for EPS compared with FGA LAIs. At least, some of this difference is a result of higher equivalent doses being used with FGAs but even when low doses are used there is still an advantage for SGAs.
Risperidone depot, however, increases prolactin, and dosage adjustment can be complex because of its pharmacokinetic profile.
Olanzapine depot is well tolerated and cost-effective, postinjection delirium sedation syndrome have been observed in one patient but was nonfatal and required three days of hospitalization.
Paliperidone depot is easy to administer even in outpatient department settings and useful in acute psychosis.
Trihexyphenidyl and propranolol may be required initially to prevent extrapyramidal side effects.
For second-generation depot, patients' tolerability and safety to oral preparation of same APs should be established.
After the patient is stabilized, they can take depot injection from a nurse or family physician and psychiatrist can see them once in 6 months.
| Direction for Future Research | | |
Further research and understanding is needed in the art of giving LAI and in developing new treatment strategies. One needs to address the optimal dose and duration of the LAI and tailor it to the needs of the patient like when the peak level and steady states are reached, how long to overlap with the oral APs, what to do if a dose is missed. Cultural variation and knowledge about fast metabolizers is very essential if patient is neither showing response nor side effects.
Clinicians need to update themselves regularly with the knowledge of LAI to feel more comfortable to prescribe them. Long-term follow-up studies are needed in naturalistic environment to prove the efficacy over the oral agents. Studies of a longer duration can add to our knowledge beyond efficacy, in terms of symptom control and extend to relapse prevention, re-hospitalization, and mortality.[18]
| Conclusions | | |
Depot preparation is an important tool in the management of schizophrenia, still its usage is limited because of perception among psychiatrists that depot preparation should be used only when there are multiple relapses. There is an evidence to show that outcomes are favorable and risk of hospitalization and relapse is reduced when depot preparation is used in early stages of schizophrenia. The cost of second-generation depot preparation can be a limiting factor, but if we consider the cost of oral pills for 1 month to depot along with long-term risk of relapse it may seem less expensive treatment.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]
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