Long term side effects of antipsychotics
What is the risk‐benefit ratio of long‐term antipsychotic treatment in people with schizophrenia?
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Long-Term Effects of Antipsychotics | Psychology Today
Donald Goff, Jeffrey Lieberman, and colleagues recently published a review article entitled “The Long-Term Effects of Antipsychotic Medication on Clinical Course in Schizophrenia” in the American Journal of Psychiatry. In this paper, the authors review the use of antipsychotics for initial treatment of psychosis associated with schizophrenia as well as the effects of long-term use, including clinical outcomes and relapse prevention. The benefits of antipsychotics in the initial treatment of psychotic symptoms are clear. Data also support long-term use of these medications to minimize the occurrence of relapse.
The authors note that up to 20% of individuals with schizophrenia may “maintain remission or partial remission for extended periods off medication.” However, it is difficult to identify this subset of individuals who might do well without long-term “maintenance” treatment.
Although antipsychotic medications are effective, some have substantial side effects, including several types of movement disorders, weight gain, and effects on sugar and lipid regulation. They may increase the risk of stroke and are associated with higher rates of death in the elderly.
We agree with the authors that for many patients with schizophrenia, the long-term use of antipsychotics, together with lifestyle changes, can be very helpful. However, what about the long-term use of these medications for symptoms other than the psychotic symptoms associated with schizophrenia? These agents are increasingly being used to treat symptoms associated with a variety of conditions, including bipolar disorder, depression, dementia, borderline personality disorder, and autism.
Some health care providers even prescribe these drugs to help with sleep or anxiety.
For these other indications, there are limited data demonstrating long-term benefit. Antipsychotic medications may help some patients for weeks or months, but longer-term use may lead to unwanted side effects. It is difficult to evaluate the risk-to-benefit ratio when long-term benefit hasn’t been demonstrated.
We teach our psychiatry residents to prescribe medications based on evidence that they work, and there are limited data supporting the long-term use of antipsychotic medications for conditions other than schizophrenia. Nevertheless, it is common to encounter patients who do not have schizophrenia but have been prescribed antipsychotics for long periods of time. Unfortunately, some of these patients are taking two or more such drugs simultaneously. It is often necessary for patients with schizophrenia to continue antipsychotics, but patients with other psychiatric disorders may be able to be weaned off these medications.
Antipsychotics are often prescribed by non-psychiatrists. It is important for non-psychiatric physicians and other prescribers such as nurse practitioners and physician assistants to review their use of antipsychotics each time they see a patient for whom these drugs are prescribed. Antipsychotics are important and powerful weapons against certain illnesses, but like any powerful treatment they need to be used carefully.
This column was written by Eugene Rubin MD, PhD and Charles Zorumski MD.
References
Goff, D.C., Falkai, P., Fleischhacker, W.W., Girgis, R.R., Kahn, R.M., Uchida, H., Zhao, J., & Lieberman, J.A. (2017). The long-term effects of antipsychotic medication on clinical course in schizophrenia. Am J Psychiatry. 174:840-849.
✚ Stop taking antipsychotics (advice from an old psychiatrist). Neuropsychiatric clinic of Professor Minutko. Article No. 8603
When are neuroleptics prescribed?
Discontinuation of neuroleptic treatment is possible and appropriate in a number of clinical situations.
Patients requiring long-term treatment may need to switch from one antipsychotic to another antipsychotic if their response to treatment has been inadequate or side effects have occurred. Some psychiatrists believe that some antipsychotics are more effective than others for psychosis - Clozapine is recognized as the most effective antipsychotic, followed by a moderately effective group consisting of Amisulpride, Olanzapine, Risperidone and Paliperidone, and then the remaining new and old antipsychotics, such as Haloperidol and Chlorpromazine. on the contrary, other psychiatrists consider haloperidol to be one of the best antipsychotics. A number of psychiatrists believe that antipsychotics can be used in severe major depression, when rapid relief of agitation, insomnia, and the prevention of the risk of suicide are needed while waiting for the action of antidepressants. nine0005
Side effects of neuroleptics
Long-term use of antipsychotics can have serious consequences, including tardive dyskinesia, weight gain, metabolic syndrome, diabetes, and cardiovascular complications.
Discontinuation of antipsychotics
When discontinuing an antipsychotic, individual circumstances must be carefully considered, including disease severity and medical history, risk of relapse and its consequences, response to treatment and prognostic factors, and the social situation of the patient. Antipsychotics should be stopped very slowly under close medical supervision. Abrupt discontinuation of treatment may lead to psychosis, which may be more severe than before treatment with antipsychotics. It is not uncommon for Clozapine to be discontinued as a result of complications such as agranulocytosis or myocarditis. Depending on the pharmacological action of the antipsychotic, several withdrawal syndromes may occur. nine0005
When evaluating the benefits and harms of taking an antipsychotic, careful consideration should be given to disease severity, treatment complications (eg, obesity), previous pattern of relapse, risk to self and others, and the psychosocial consequences of relapse.
Repeated episodes of psychosis worsen the long-term prognosis. Because the risk of recurrence after a second episode is high, most physicians recommend long-term treatment.
When can antipsychotics be safely discontinued?
Antipsychotics can be safely discontinued if antipsychotics (eg, low-dose quetiapine) have been used for anxiety or sleep disturbance and ongoing treatment is not required or undesirable, antipsychotics have been used to treat behavioral disturbances in dementia but are no longer needed because of -for the correct correction of behavioral behavior or the positive impact of the patient's environment. In addition, neuroleptics should be discontinued if antipsychotics have been tested for indications not covered by the instructions and have not been effective. nine0005
Withdrawal of antipsychotics after severe depression
Patients who have experienced psychotic depression and have responded to a combination of antidepressants and antipsychotics with or without electroconvulsive therapy can often continue to be treated with antidepressants alone.
There are no clear recommendations as to when antipsychotics can be discontinued in these patients. However, after the patient has recovered for some time, it is often possible to gradually reduce the dose while continuing to monitor the patient's mental state (especially if serious risk factors such as suicidality were initially present). nine0005
Discontinuation of antipsychotics under medical supervision
Under the supervision of a psychiatrist, antipsychotics are discontinued in the following cases: after the first episode of psychosis, there was a qualitative remission within a year (up to 40% of patients who survived one episode of psychosis can remain healthy after stopping antipsychotic drugs or at least need only low doses), in bipolar mood disorder when antipsychotics are no longer needed, especially if lithium monotherapy is appropriate. If there have been two episodes of psychosis, then an antipsychotic is required for at least two years. Antipsychotics can also be discontinued under medical supervision if there has been a complete recovery from drug-induced psychosis and clinical evaluation indicates that antipsychotic treatment is no longer needed (eg, drug use has been stopped).
Many psychiatrists believe that if there have been several episodes of psychosis or recovery was incomplete, then permanent treatment with antipsychotics is recommended, since when the drug is stopped, the psychosis is more likely to worsen or recur. nine0005
Withdrawal of long-acting antipsychotics
Some antipsychotics (especially depot injections) have a long half-life and are unlikely to be associated with significant withdrawal symptoms.
Switching antipsychotic
There are a number of clinical situations in which switching from one antipsychotic to another is considered. Before switching, a psychiatric examination is recommended, especially in difficult clinical situations or when an urgent switch is needed. Changing antipsychotics is recommended when there is an inadequate clinical response to acute symptoms despite dose optimization and adequate duration of treatment. Changing the neuroleptic is possible if there is poor control of chronic symptoms of psychosis and functional impairment persists during maintenance therapy, if there has been a relapse despite adequate preventive or maintenance treatment of psychotic illness.
Persistence of certain symptoms of psychotic illness (eg, negative symptoms and cognitive dysfunction) despite adequate doses of a single antipsychotic that may respond better to an alternative neuroleptic is also an indication for a change of medication. Unacceptable side effects at low therapeutic doses before a clinical response in susceptible individuals (eg, extrapyramidal effects in Asian patients) also require consideration of switching to antipsychotics with a lower risk of side effects. The need to change the antipsychotic drug due to a physical complication (eg, ziprasidone is contraindicated in cardiovascular disease, antipsychotics that cause severe hyperprolactinemia are contraindicated in breast cancer) are known reasons for switching antipsychotics. Poor adherence to treatment is an indication for switching from an oral antipsychotic to a long-acting injectable depot. nine0005
Switching from one antipsychotic to another is not necessarily a panacea. During the switch, an exacerbation of the disease may occur and new side effects may appear.
When a switch is made due to an inadequate response, it is important to ensure that the dose of the first antipsychotic has been optimized, that the patient has been on treatment for an adequate period of time, and that the patient is adhering to the regimen and tolerating the course of treatment.
These factors should be taken into account when changing antipsychotics
The choice of a new drug will be determined in part by the reasons for the switch, but will also need to take into account the likely efficacy, side effects, dosing regimen, and patient or caregiver preference.
Withdrawal syndrome
Depending on the pharmacology of the antipsychotic, switching from one antipsychotic to another can lead to withdrawal syndromes, especially withdrawal of anticholinergics with drugs such as Quetiapine, Clozapine, Chlopromazine and Olanzapine. Switching from one antipsychotic to another (for example, when looking for a drug with a lower risk of weight gain) can lead to loss of efficacy and withdrawal symptoms.
nine0005
Clozapine withdrawal
When a patient is switched from clozapine to another antipsychotic drug, relapsing psychosis and other serious withdrawal effects may occur, regardless of which clozapine drug is switched to. Clozapine should be discontinued under the supervision of a psychiatrist. The dose should be gradually reduced, and not stopped abruptly. However, sometimes this may be unavoidable if, for example, we observe agranulocytosis.
How to stop an antipsychotic
Unlike switching antidepressants, a drug-free period between stopping the first antipsychotic and starting the second is not recommended due to the risk of relapse. When switching from an oral antipsychotic to a depot, a depot to a depot, or a depot to an oral antipsychotic, special instructions must be followed.
Direct switching
Although it is possible to stop the first drug and immediately start the second the next day, this can lead to withdrawal symptoms and possible drug interactions.
When the first antipsychotic is aripiprazole or brexpiprazole, one can immediately switch to them, since both of these drugs have a very long half-life and do not have anticholinergic effects. nine0005
Cross-titration
Available data in the literature indicate little difference in the risk of relapse with immediate or gradual discontinuation or switching of antipsychotics. Most psychiatrists use a cross-titration strategy. (reducing the dose of the first neuroleptic with the introduction of the second). A slower approach to titration is to continue the first antipsychotic for a period at its usual dose while gradually increasing the therapeutic dose of the second antipsychotic. Then you can gradually reduce and stop taking the first antipsychotic. With this approach, the risk of relapse is minimized, but additional side effects may occur. nine0005
When it is necessary to switch from one antipsychotic to another during the treatment of psychoses, clinicians need to have some understanding of the pharmacokinetics and dynamics of antipsychotics in order to plan and carefully manage regime change.
This usually involves taking both drugs at the same time. Discontinuation and switching of neuroleptics can lead to serious consequences, especially relapse of psychosis, which can carry serious risks and worsen long-term prognosis. Withdrawal syndromes associated with cholinergic and dopaminergic effects may occur depending on the characteristics of the antipsychotics being taken. nine0005
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Long-term side effects of levodopa - Center for Extrapyramidal and Cognitive Disorders
For about 50 years, levodopa (L-DOPA, the levorotatory isomer of the amino acid deoxyphenylalanine) has been the most effective treatment for Parkinson's disease.
In terms of effectiveness, it is ahead of any other anti-Parkinsonian drug and even neurosurgical intervention. It provides the most guaranteed anti-Parkinsonian effect, causing improvement in almost 100% of patients with Parkinson's disease. Not a single patient with Parkinson's disease who seeks to maximize the period of his active life can avoid its intake. Levodopa is considered the "gold standard" for the treatment of Parkinson's disease. It increases the life expectancy of patients. To date, there are no convincing data on the neurotoxic effect of levodopa. Moreover, the ability of small doses of levodopa to exert a neuroprotective effect cannot be ruled out. nine0005
After oral administration, levodopa enters the brain and is converted by functioning nerve cells into dopamine, compensating for its deficiency. Modern drugs (such as Nakom or Madopar) contain a combination of levodopa with an inhibitor of the enzyme DOPA-decarboxylase, which blocks the metabolism of levodopa in peripheral tissues, resulting in a large part of levodopa reaching the brain and reducing the likelihood of side effects associated with the peripheral action of the drug.
In the early stages of Parkinson's disease, even small doses of levodopa often have a significant effect, almost completely eliminating the symptoms of parkinsonism. Unfortunately, a few years after the start of treatment with levodopa in a significant proportion of patients, the reaction to the drug changes: the duration of the action of a single dose decreases, violent movements (dyskinesias) appear. nine0005
The patient takes the prescribed single dose of levodopa, it begins to act after 40 minutes - the patient begins the "on" period, characterized by a decrease in the symptoms of parkinsonism, and after 3-4 hours, and subsequently even faster - after 2- 2.5 hours - the effect of the drug weakens - a period of "off" begins with a decrease in motor activity. Sometimes "on" and "off" are accompanied by involuntary (violent) movements of a different nature. During the day there are also stiffenings when walking, when for a few seconds or minutes the patient cannot move.
For patients with this disorder, turning or passing through a relatively narrow doorway may be particularly difficult. Fluctuations in motor activity, which are possible in a wide range - from excessive motor activity at the peak of the dose to a sharp weakening of motor capabilities during the "off" period, are called motor fluctuations in the medical literature. nine0005
There are several types of motor fluctuations. The phenomenon of "exhaustion" of the end of the dose is characterized by a gradual predictable partial return of the symptoms of parkinsonism by the end of the next dose of levodopa. Many patients, as the effect of a single dose of levodopa wears off, also note depression of mood, anxiety, sweating, palpitations, increased pain, etc. ("non-motor fluctuations").
Over time, the patient's transition from the "on" state to the "off" state becomes more and more brief and abrupt, which is referred to as the "on-off" phenomenon. nine0005
Sometimes the "off" period comes on suddenly, regardless of when the drug is taken.
In addition to the above fluctuations, delayed development of “on” or complete absence of “on” is possible, when taking the next dose is not accompanied by an improvement in clinical symptoms or does not occur quickly enough.
Against the background of "on" (at the peak dose of levodopa), rapid "dancing" (choreiform) movements may occur, mainly involving the upper half of the body ("peak dose dyskinesia"). This is a kind of limiter, requiring the weakening of dopaminergic therapy, since increasing the dose will lead to an increase in dyskinesias. This phenomenon is based on hypersensitivity of dopamine receptors. nine0005
Off-period dystonia is a violent, prolonged, often painful contraction of the muscles of the lower extremities, often with plantar flexion or tucking of the foot. It usually appears at night or in the morning before the next dose of the drug and decreases with longer dopaminergic stimulation, achieved by prescribing a sustained-release levodopa drug (Madopar GSS), a long-acting dopamine receptor agonist, or a combination of levodopa with a DOPA decarboxylase inhibitor and a catechol inhibitor.
-Omethyltransferase entacapone (Stalevo). nine0005
y bSince the risk of fluctuations and dyskinesias depends on the total dose of levodopa preparations, it is customary to prescribe them only with a real decrease in the patient's functional capabilities, which interferes with his professional or daily household activity.
In younger patients (up to 60 years of age), fluctuations in the effect of levodopa develop faster, so they try to delay the time of prescribing levodopa in this age group by starting treatment with other antiparkinsonian drugs: dopamine receptor agonists (ropinirole, pramipexole, piribedil, rotigotine) , monoamine oxidase inhibitors - rasagiline (Azilect) or selegiline (Yumex). Additionally, to enhance the effect, amantadine and an anticholinergic (especially with rest tremor) or a combination of all of these drugs can be prescribed. And only when they no longer give the desired effect and do not provide sufficient patient mobility, small doses of levodopa are added to them.
However, some experts believe that excessive delay in the appointment of levodopa is not the best tactic in the management of patients, as it is often accompanied by insufficient control of symptoms. Meanwhile, adequate correction of motor functions is the main guarantee of the best long-term results of treatment. nine0005
In the elderly, who are at lower risk of fluctuations and dyskinesias, it is common to start levodopa immediately. In this case, the minimum effective dose should be adhered to, which can be achieved by adding dopamine receptor agonists, type B monoamine oxidase inhibitors or amantadine.
"Off" periods and dyskinesias can be excruciating for patients, and they may be tempted to relieve their condition by taking an emergency dose of levodopa or another antiparkinsonian drug. Often, in a vicious circle, this leads to an aggravation of the instability of the patient's condition. Because of this, any changes in the treatment regimen, especially with fluctuations, should be agreed with the attending physician.
Correction of fluctuations and dyskinesias is a difficult task even for an experienced specialist, and it can be solved only with close cooperation between the doctor and the patient. nine0005
The goal of adjusting the treatment regimen is to maximize the duration of the "on" period in the absence or minimal presentation of dyskinesias. Filling in a daily activity diary by the patient at 1-hour intervals can help the clinician analyze the relationship between the “off” period and dyskinesias, as well as their occurrence relative to the timing of medications.
When the duration of action of levodopa decreases (the “end-of-dose exhaustion” phenomenon), most specialists first resort to splitting the dose of levodopa (reducing the single dose with a shortening of the interval between doses of the drug) and switching from an immediate-release drug to a sustained-release drug (Madopar GSS) . In addition, the effect of levodopa can be enhanced by improving its absorption. To do this, the drug is taken at least 60 minutes before a meal and not earlier than 2 hours after a meal.
In addition, they reduce protein intake during the day (amino acids formed during the breakdown of food proteins compete in the intestines with levodopa for absorption). If this does not work, one of the dopamine receptor agonists (preferably controlled-release), the catechol-O-methyltransferase inhibitor entacapone (switching to Stalevo), or a monoamine oxidase inhibitor type B must be added sequentially.
The sequence of prescribing drugs is determined individually, including taking into account the risk of side effects in each individual patient.
Freezes that develop during the “off” period respond to techniques that reduce the “off” phase. It is useful to teach the patient how to overcome freezing by walking in place, unusual dance movements, stepping over an imaginary line drawn on the patient's path, or using a special cane with a thin metal bar that folds down at the bottom, stepping over which the patient can start moving. nine0005
Other recommendations for freezing:
• stop trying to continue driving;
• try to shift from one foot to the other;
• slightly bend your knees, lift your foot off the floor and step forward;
• count "one, two, three" or tell yourself "left-right, left-right";
• hum a rhythmic melody;
• imagine the sound of footsteps on the pavement and raise your leg to take a step;
• try to imitate the walking of the person in front; nine0171 • if you have a problem getting through a narrow space, try to look beyond it: imagine where you will be when you pass this space.
In cases where the transition from "on" to "off" becomes unpredictable, it is possible to return to less frequent use of relatively large doses of levodopa ("dose piling"). This will lead, on the one hand, to an increase in the period of "on" in the daytime period, when the patient needs to be active; on the other hand, the “off” period will also increase, but will move to the evening and become more predictable. Treatment of on-off fluctuations becomes more difficult when the on-period is accompanied by dyskinesias. In these cases, there may not be an unambiguously satisfactory solution, and the patient himself must decide whether to put up with hyperkinesis during the "on" or suffer from a long period of "off". Usually patients choose the first. nine0005
In cases where drugs fail to achieve sufficient effect, resort to stereotaxic operations (constant stimulation of certain areas in the basal ganglia) (see below). An alternative may be subcutaneous administration of apomorphine, the introduction of a gel with levodopa / carbidopa (duodopa) into the duodenum.
But sometimes it is not possible to completely get rid of motor fluctuations. Then it remains to adapt to them: you do all the things you need during the hours when you feel better, spend the rest of the hours doing activities that do not require movement: reading, watching TV, listening to the radio. nine0005
In domestic clinical practice, patients with Parkinson's disease are often treated with drugs whose effectiveness in this disease has not been convincingly proven. Often these are the so-called "vascular drugs", often administered intravenously by drip. Their appointment is often justified by naive and archaic ideas about the connection of Parkinson's disease with "bad vessels of the brain", which in most patients, even the elderly, do not suffer significantly. The positive experience of their use, if it exists, is explained by nothing more than the placebo effect. nine0005
The placebo effect is achieved by the patient's faith in the doctor, by misrepresented or inaccurately perceived information, by the power of tradition, and sometimes by the patient's desperation in the methods of classical medicine.
Parkinson's specialists are well aware that a significant proportion of patients respond well to placebo, but this effect is never sustainable. Most importantly, ineffective drugs and other treatments do not prevent adequate treatment of a disease that, if delayed, can have adverse long-term consequences. nine0005
In general, patients with Parkinson's disease should be cautious when using any medication, some of which carry the risk of worsening their condition. First of all, this applies to neuroleptics, such as haloperidol, triftazin, etaperazine, clopixol, olanzapine (Zyprexa), risperidone (Rispolept). Even such relatively mild drugs as sulpiride (Eglonil), thioridazine (Sonapax), teraligen, when taken regularly, can cause significant deterioration.
The same can be said about a number of drugs that are widely used in neurological and therapeutic practice, but can block dopamine receptors and increase the symptoms of parkinsonism: cinnarizine (including combined preparations of cinnarizine and piracetam, for example, Omaron or Phezam), metoclopramide (Cerucal), pipolfene .
Iron preparations prescribed for iron deficiency anemia can reduce the effectiveness of levodopa and often require an increase in its dose.
Be careful with drugs that cause sedation, including sleeping pills, especially if they are long-acting (eg phenazepam). When using them, inform your doctor about the severity of the sedative effect, the possible increase in symptoms during the day. On the other hand, such "nootropic" drugs as piracetam or fenotropil can cause arousal in some patients. nine0005
Finally, it should be borne in mind that during surgical interventions for concomitant diseases, inhalation anesthetics are often used for anesthesia - drugs with a strong sedative effect that can cause an artificial coma, which is necessary for surgical intervention. In older people, they can cause confusion. Some surgeries can be performed under the influence of less dangerous drugs, in some conditions you can do without surgery. Ask your doctor about alternative treatments before opting for surgery.
nine0005
The list of drugs that can cause deterioration in patients with Parkinson's disease is very extensive, so it makes sense to consult a neurologist before starting a new drug on a regular basis, even if it is prescribed for a different disease.
Rapid progress in the study of the pathogenesis of Parkinson's disease, as well as the development of the latest medical technologies (in particular, the technique of planting stem cells that can take the place of dying cells, or genetic therapy) allow us to hope that in the next decade a way will be found to significantly slow down the progression of this disease . nine0005
To get the most out of your doctor's visit, try these simple tips:
• Most doctors welcome information about your condition. This will help you to participate in making decisions about therapy, and you will be able to articulate your complaints more precisely.
• Make a list of questions you have with your doctor ahead of time.
• Do not put off seeing your doctor for too long, especially if you feel your treatment is worsening or getting worse.
