Schizophrenia Medication and Side Effects
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Medications for Schizophrenia fall into three categories
- Major Tranquilizers (see full table below) –also called anti-psychotics. The common ones that are currently used include Chlorpromazine (Thorazine), Haloperidol (Haldol), Perphenazine (generic only), Fluphenazine (generic only), Risperidone (Risperdal), Olanzapine (Zyprexa), Quetiapine (Seroquel), Ziprasidone (Geodon). Aripiprazole (Abilify), Paliperidone (Invega)
- Mood Stabilizers-including Lithium and anti-seizure medications (See Table below)
- Minor Tranquilizers-also called long acting benzodiazepines (Klonopin, generic clonazepam)
- Anti-inflammatory medications
The Major Tranquilizers (Antipsychotics)
When used consistently, in appropriate doses, and with monitoring of side effects and compliance, the major tranquilizers can significantly enhance the quality of life for many patients with Schizophrenia. Ideally, they are used in combination with a strong and calm support network, measures to reduce inflammation and infection in the body, good diet, and avoidance of over the counter stimulants and drugs of abuse. In this type of setting, dosages can be minimized and increased as needed during episodes.
There are five main areas of concern with the major tranquilizers: metabolic syndrome, neuroleptic malignant syndrome, tardive dyskinesia, agranulocytosis, and in the elderly with psychotic conditions, premature death.
There are various definitions of metabolic syndrome, but essentially it a group of symptoms that increase your risk for heart disease, type II diabetes and stroke. It involves weight gain (with its attendant risks of heart disease and musculoskeletal problems), resistance to insulin (moving one toward diabetes), inflammation, and elevated blood lipids (e.g., cholesterol and triglycerides). The majority of psychiatric medications carry this risk, and this argues again, for the Whole Psychiatry approach, in which medication is reduced and lifestyle, nutrients, hormonal supplements, immune regulation are part of the program. The Whole Psychiatry approach sharply reduces the risk of developing the metabolic syndrome, as well as other risks of chronic illness (e.g., dementia, osteoporosis).
Neuroleptic Malignant Syndrome
Neuroleptic malignant syndrome (NMS) is a poorly understood, uncommon condition that can be fatal. It appears in patients who have been treated with antipsychotics, and seems to be independent of dosage and length of treatment. These patients present with symptoms of muscle rigidity, elevated temperature, sweating, blood pressure and pulse changes, as well as altered consciousness. It is treatable, but must be recognized quickly for treatment to succeed. The two essential symptoms are the muscle rigidity and elevated temperature. Treatment of NMS requires intensive care unit monitoring of vital signs, kidney function, etc.
Tardive dyskinesia is only one of a variety of muscle movement disorders caused by the antipsychotics. Other disorders include: sudden dystonia, (sudden abnormal muscle movements and spasms), akathisia (an extremely intense form of restlessness that causes people to actually want to “jump out of their skin”–in some patients this agitation can be mistaken for a worsening of the psychotic symptoms, leading to more medication, increased agitation, and even suicide. It is easily and quickly treatable within minutes, once recognized); and Parkinsonism (minimal facial expressiveness, stiff walking movements, and characteristic movements of the hands). All of these movement disorders are treatable and reversible, with the exception of tardive dyskinesia (although there is new evidence that a medication called Aricept-used for dementia, can help, as can certain amino acids in a supplement called Tarvil).
Tardive dyskinesia was thought to occur only after prolonged treatment with antipsychotics, hence the descriptor tardive (late or tardy). ‘Kinesia’ refers to the movement of the muscles, and the prefix ‘dys’ means abnormal. Unfortunately, recent studies and case reports indicate that the onset of this often permanent condition does not seem to be related to time. In fact, tardive dyskinesia has been known, on rare occasions, to occur after the first dose of an antipsychotic medication.
Patients who are most at risk for tardive dyskinesia seem to include the elderly, women, people with depressive disorders, and those with previous brain damage. Frequently, the condition improves and is not permanent if the medication is discontinued, but this may take as long as one or two years. In a significant number of patients it is permanent.
Tardive dyskinesia must be differentiated from the other movement disorders listed above, as the implications for treatment are different. The other disorders are usually easy to treat. It should be emphasized that tardive dyskinesia is not fatal, but is often permanent. Because of the possible permanence of this side effect, the major tranquilizers should only be used in bipolar disorder, schizophrenia, schizoaffective disorders (a combination of depressive and schizophrenic symptoms), Tourette’s syndrome (muscle and vocal tic disorder), and perhaps obsessive-compulsive disorder with tics, which has responded poorly to standard medications. A sudden episode of schizophrenic psychosis can usually be treated and prevented very effectively with these medications. There is some evidence that the newer ‘atypical antipsychotics’ such as Risperidone (Risperdal), Olanzapine (Zyprexa), Quetiapine (Seroquel), Ziprasidone (Geodon). Aripiprazole (Abilify), Paliperidone (Invega) are less likely to cause these effects. Clozaril (see below) is the only anti-psychotic that does not carry with it the risk of tardive dyskinesia. However, Clozaril does carry with it the risk of agranulocytosis.
Agranulocytosis is mainly a concern with Clozaril (occurring in 1.3% of those treated), but may occur with Mellaril, Prolixin, Serentil, Thorazine, and Trilafon as well. It is an uncommon condition that can be caused by many medications used in general medicine. It occurs when the medication causes the body to stop producing a certain type of infection-fighting blood cell. It is potentially life threatening unless detected early. For this reason, weekly monitoring of blood counts of patients using Clozaril (and less frequently, other medications) is necessary.
One might wonder why anyone would even consider the use of a medication like Clozaril. The answer lies in three facts: Clozaril is the first antipsychotic that does not cause tardive dyskinesia. Clozaril has been statistically shown to be more effective than the standard antipsychotic medications, particularly in treatment-resistant schizophrenia and schizophrenia accompanied by the negative symptom domain. And finally, Clozaril may also reduce the risk of suicide. It is therefore quite a breakthrough for treatment-resistant schizophrenia. Clozaril was the first of the atypical anti-psychotics–a new group of antipsychotic medications that are possibly more effective due to their selective action at the level of the limbic system (the mediator of emotional response). These new medications [(Risperidone (Risperdal), Olanzapine (Zyprexa), Quetiapine (Seroquel), Ziprasidone (Geodon). Aripiprazole (Abilify), Paliperidone (Invega)] have little effect on the part of the brain that controls muscle movement (the striatum), and therefore seem to lack the troublesome muscular side effects. Because compliance is usually such a problem in schizophrenia, long acting intramuscular forms of many medications are available.
How and Where Do the Major Tranquilizers Work?
These medications block the action of the chemical neurotransmitter dopamine, which inhibits nerve cell activity; these drugs seem to target certain areas of the brain that are under dopamine control. This initially results in increased rates of firing in certain areas of the brain; however, after long-term use, when the antipsychotic effect is clinically evident, these nerve pathways are almost completely inactive. It is commonly believed, but not yet proven, that this action is the reason for both the beneficial and adverse side effects of these medications. The specific areas of the brain whose nerve cells communicate via dopamine include:
- The area that connects the midbrain, limbic system (controlling emotion), and the frontal cortex (controlling executive activity, social awareness, reward and pleasure, and planning), called the mesolimbic, and mesocortical nerve pathways. The action of these medications on this nerve pathway probably accounts for the antipsychotic effects of these medications. These medications also affect the dopamine-containing nigrostriatal pathway, which accounts for the movement disorders associated with these drugs. Medications are currently being developed that may affect only this pathway (Clozaril is such a medication), eliminating many of the side effects caused by the action of these medications on the following areas.
- The striatum, which controls movement and muscle tone. Drug effects in this area are responsible for the side effects of muscle stiffness, movement disorders, as well as NMS (discussed above) caused by these medications.
- The hypothalamus and pituitary gland, which control hormonal regulation of appetite, milk production, sexual function, and temperature regulation. Medication action in this area is responsible for side effects such as breast enlargement, weight gain, and NMS.
- The reticular formation, which controls arousal. Medication action in this area accounts for the reduction in emotional reactivity to external stimuli, perhaps improved sensory filtering, as well as sedation.
The Mood Stabilizers
The mood stabilizers include a small group of chemically diverse medications that are useful primarily in the bipolar disorders, although they do have uses in schizoaffective disorders (combination of schizophrenia and a mood disorder), and schizophrenia with a strong obsessive component. The group includes lithium carbonate (Eskalith, Cibalith, Lithobid), carbamazepine (Tegretol), and valproic acid (Depakote). Klonopin, commonly used in the same disorders as the mood stabilizers, but not a mood stabilizer itself, is an antimanic, antipanic agent that is included in the minor tranquilizer class. See the Bipolar section for more information about these medications.
Valproic acid (Depakote) is an antiseizure medication. It is used to treat schizoaffective disorder, panic disorder, some dissociative disorders, borderline personality disorder, and to assist in withdrawal from the minor tranquilizers, such as Valium and Xanax, among others.
Risks and Side Effects of Valproic Acid
Valproic acid, a fatty acid, has been in use for seizure disorders in Europe since the 1960s. As a result of this long history, certain risks have been found with the use of this medication. Liver failure, which can result in death, has been reported. For this reason, I always have my patients use a combination of N-acetylcysteine, R-Lipoic Acid and Selenium, as a liver protector (helps metabolize the valproic acid), promoter of glutathione production (a great anti-oxidant and detoxifying agent in the body), neuroprotector, anti-anxiety and perhaps anti-depressant combo.
Nevertheless, liver failure is rare, and having used valproic acid in my practice for over 20 years, I have never seen this occur. At particularly high risk for liver failure, however, are patients on multiple anticonvulsants (e.g., Tegretol or Klonopin [clonazepam]), those with inborn disorders of metabolism, organic brain disease, mental retardation in the presence of a severe seizure disorder, and children (particularly under age 2). As a person advances in age, he or she is significantly less likely to develop this problem.
Valproic acid can also cause decreased platelet counts, which results in abnormal bleeding and bruising. Because of these rare toxic effects, certain tests of liver function and platelets must be monitored both before and during treatment. Patients must report easy bruising, fatigue, muscle weakness, lethargy, swelling of the face, loss of appetite and vomiting to the physician. All of these problems usually occur in the first six months of treatment, if they occur, and thus monitoring should be more intense during that period.
Common side effects of valproic acid include nausea, vomiting, indigestion, diarrhea, tremor, sedation, temporary hair loss, depression, weakness, and abnormal menses.
The blood levels of valproic acid necessary for seizure control (the original use of this drug) may be different than the levels needed for the treatment of the various psychiatric conditions mentioned above. Sufficient research has not been conducted to address this question. Often, it takes several weeks to obtain the best regimen of valproic acid in an individual patient. Certain preparations are slowly released (e.g., sprinkle capsules for children) and better tolerated, but are only available in low strength, requiring that you take numerous pills, at least until your final dose is determined and then larger strength tablets can be used. The dosage range is wide, varying from 125 mg three times per day to as high as 750 mg three to four times per day. As with lithium and carbamazepine, the dose of medication is less important than the actual level of medication in the blood stream.
Anti-Psychotic Medications used in Bipolar Disorder and Schizophrenia
|Daily dosage||Sedative effects||Comments|
|2-30mg||Low||Possibly less weight gain, possible use in bipolar depression (recently refuted)|
|300-900 mg||High||No tardive dyskinesia
Risk of possibly fatal blood
disorder requires close monitoring
|5-10 mg 4X daily||High||Mainly used for nausea despite same risks of other drugs in this class|
|20mg-80mg||Low||Stimulating in low doses|
|0.5-5 mg||Low||Also used in Tourette’s syndrome (uncontrollable tics and vocal utterances). No evidence that higher doses are more effective|
|10-800 mg||High||Some data indicate less likelihood to cause tardive dyskinesia|
|5-200 mg||Low-moderate||Off the market|
|2.5-30mg||High||Severe rapid weight gain, but highly effective|
|1-10 mg||Low||Used in Tourette’s syndrome|
|1.5-18mg||High||Active metabolite of risperidone extrapyramidal symptoms, tachycardia and akathesia|
|1-40 mg||Low||Can be administered on once-monthly basis|
|1-4 mg 2x/day||Moderate||More effective for negative symptoms;
less extrapyramidal symptoms
|5-10mg 2x/per day||High|
|50-100 mg 3x/day||High|
|25-800mg||High||Mania, anxiety (COMT SNP positive on both allelles), bipolar depression|
|1-20 mg 1-2x/day||Low|
|6-12mg Olanzapine/25-50mg fluoxetine||High||Approved for both phases of bipolar disorder; weight gain|
|25-800 mg/day||High||The first known antipsychotic|
|2-32 mg 1-2x/day||Low|
Anti-inflammatory medication, and miscellaneous medications
Because the chemistry and normal function of the brain is so dependant on a normal immune system, and because the standard medications for schizophrenia lead to a heightened state of inflammation and weight gain, it makes sense that calming the immune system in the brain, through the use of anti-inflammatory medication might be helpful. In the Whole Psychiatry approach, we can do this via diet, supplements, correcting hormonal imbalances, and correcting the detoxification and gastrointestinal systems. Since this may be too difficult for many people with schizophrenia, particularly if they are not in a highly structured and supportive environment founded on healthy lifestyle principles, the use of anti-inflammatories can be considered. This approach is most likely to be helpful within the first few episodes of the illness. In keeping with this theory, Cox-2 inhibitors (e.g., celocoxib) have been tested in preliminary clinical trials for schizophrenia and depression, showing favorable effects compared to placebo (Muller and Schwarz et al 2009).
Statins are also anti-inflammatory agents and thus similar to the Cox-2 inhibitors, which have shown some ability as adjuncts to improve the symptoms of schizophrenia in preliminary studies. The statins are also known to decrease C-reactive protein (CRP)-a marker of inflammation, which has been shown to be elevated in a study of individuals with schizophrenia. Fan et al (2007) demonstrated in a small study in patients with schizophrenia that higher than normal levels of CRP (>0.50 mg/dl) was associated with marked negative symptoms and higher total PANSS scores (a test measuring symptoms and signs of schizophrenia).
Ondansetron is a serotonin (5-HT3) receptor antagonist that is generic and widely used to prevent nausea and vomiting in patients receiving chemotherapy for cancer. Glaxo did a small study on it as an antipsychotic in the 1980s. Since then, several small studies have suggested that it is effective as an adjunct drug in improving the symptoms of schizophrenia.
Schizophrenia is best considered as a disorder in which inherited neurobiologic vulnerabilities interact with psychological, social, and developmental processes. These processes may be somewhat protective in that a supportive family can delay relapse. All too often however a vicious mutually interacting cycle of deteriorating cognitive, vocational and social function develops, which probably contributes further to the neurological dysfunction.
Despite the clear evidence from genetic studies that there is a strong heritable predisposition to schizophrenia, no hallmark symptom or marker of any type has been identified. Cognitive deficits are widespread, present at a young age, and may worsen with time. Neither the much heralded brain imaging studies, nor electrical and biochemical studies have identified a clear pattern of deficits that could be used as the sine qua non of schizophrenia. Research regarding non-pharmacologic treatment is lacking, and funding is being reduced. Finally, and most importantly, clinicians are beginning to recognize that the treatment of schizophrenia must be multimodal and continuous to be effective at reducing relapse and human suffering.
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