Monday, March 14, 2005
Paper 2
Schizophrenia remains one of the most severe, chronic, and debilitating psychiatric disorders. Generally beginning in late adolescence or early adulthood, it effects approximately 1% of the population. The disease is characterized by a variety of symptoms along four dimensions: positive symptoms, negative symptoms, cognitive impairments, and disturbances in mood and affect. Life expectancy….
The first medications to treat schizophrenia were introduced in the 1950s. While these early, or “conventional” antipsychotics have been very effective at treating the positive symptoms of the disease, they also tend to cause devastating extrapyramidal motor symptom side effects (EPS) and often irreversible tardive dyskinesia (TD). The symptoms of EPS mimic that of Parkinson’s Disease and include things such as tremor, akathisia, and acute dystonia. TD causes uncontrollable facial and tongue movements like chewing and grimacing and hyperkinetic activity in the distal extremities.
Treatment with pharmaceutical agents like haloperidol, thioridazine, or chlorpromazine control the psychotic aspects of schizophrenia by blocking dopamine type 2 (D2) receptors in the mesolimbic pathway in the brain (402). Unfortunately there are also D2 receptors in other areas of the brain, specifically the substantia nigra and basal ganlia that these agents will block as well which initially cause EPS. With chronic blockade of D2 receptors in the nigrostriatal pathway, EPS will progress to TD at a rate of 4% per year of exposure to the antipsychotic agent.
The development of movement related side effects further increase the social stigma that schizophrenic patients face, making it very difficult to encourage patients to remain compliant with these agents for any length of time. Once patients discontinue treatment psychosis will typically relapse at a rate of approximately 10% per month, so that 50% or more have relapsed by 6 months after the medication is discontinued. (408)
In 1990, clozapine, the first of the new or “atypical” antipsychotics was approved by the FDA for the treatment of schizophrenia. The new agents were given the title of “atypical” because of their similar clinical properties, most noteably their low rates of EPS and efficacy for treating negative symptoms of schizophrenia. Pharmacologically speaking, the medications in this class have chemical structures that are very different from one another, howver they all act on the same receptors in the brain.
Like their conventional counterparts, the atypicals treat the positive symptoms of schizophrenia by blocking D2 receptors. In addition to D2 receptor blockade, the atypicals block serontonin 2A (5HT2A) receptors as well, which helps to explain why these agents are also effective at treating the negative, cognitive, and affective symptoms of schizophrenia. (416)
This antagonism of the 5HT2A receptors in the nigrastriatal pathways of the brain is also thought to be responsible for the relative lack of EPS seen with the atypical agents. 5HT2A antagonism in the nigrostraital pathway leads to the reversal of D2 receptor blockade in the area and blocking 5HT2A receptors also stimulates the release of dopamine in the nigrostriatial pathway. With an increase presence of dopamine in the substansia nigra, the extrapyramidal side effects are virtually eliminated. (417).
As a class, the atypical antipsychotics, have virtually taken over the treatment of schizophrenia, and account for approximately 80% of all antipsychotics prescribed in the United States. (Tandon) There are currently six atypical antipsychotics approved for use in the United States- clozapine (Clozaril), olanzapine (Zyprexa), qutiapine (Seroquel), risperidone (Risperdal), zisprazadone (Geodon), and aripiprazole (Abilify). Clozapine remains the most effect agent available for treating all four dimensions of schizophrenia symptoms. However, it has been associated with agranulocytosis, a rare but life threatening side effect, so its use is reserved for treatment resistant patients.
As experience with the atypical antipsychotics grows, other similarities amongst the different drugs in the class are becoming evident as well. Perhaps the most other most notable similarity with these agents are the metabolic disturbances that often arise in patients that take them. Increased rates of type 2 diabetes, hyperlipidemia, and obesity have all been associated with atypical antipsychotic treatment.
Diabetes:
Type 2 diabetes is a serious health problem in the United States. In 2002 the CDC estimated that approximately 6.3% of the population, or 18.2 million Americans suffer from the disease, and 90% of those have type 2 diabetes (CDC). People with diabetes have a risk of developing heart disease that is 2-4 times greater than that of the general population and diabetes is currently the sixth leading cause of death in the United States (CDC).
Schizophrenia itself appears to carry an increased risk of diabetes unrelated to treatment with antipsychotics. A study of first episode, drug-naïve schizophrenia patients found high rates impaired glucose metabolism, a precursor for the development of type 2 diabetes. Impaired fasting glucose tolerance was observed in 15.4% of the patients with schizophrenia, compared to none of the matched healthy comparison subjects (sas).
Use of antipsychotic medication also appears to increase the risks of developing type 2 diabetes. Rates of diabetes have been found to be higher in patients treated with both typical and atypical antipsychotics than in the general population. A retrospective analysis of more than 56,000 patients treated with antipsychotics (both conventional and atypical) estimated the annual incidence rate of diabetes to be 4.4%, a rate considerably higher than the expected 6.3 cases per 1000 people annually the general U.S. population. (lelise).
The risks may be even greater for younger patients treated with antipsychotic medication. The rate of diabetes for people between the ages of 20-39 in the general U.S. population is 1.1%. Rates of diabetes between 6.2-8.7% were observed in a retrospective analysis of more than 4000 people between the ages of 20-39 who received treatment with a conventional or atypical agent. (sernyak)
There is also evidence available to suggest that the use of atypical agents may be associated with a higher rate of diabetes compared to the use of conventional agents. After controlling for the effects of age, a retrospective comparison of 38,632 patients on antispcychotic therapy: 15,984 on conventional agents and 22,648 on atypical agents, found that paitents who received atypical neuroleptics were 9% more likey to have diabetes than those who receivd conventional agents. (sernyak)
Among the atypical agents, clozapine and olanzapine appear to carry the greatest risk of causing abnormalities in glucose metabolism. At the end of a 5 year study of 82 patients being treated with clozapine, 30 (36.6%) were found to have been diagnosed with type 2 diabetes (Henderson). Another study involving almost 6000 patients using either olanzepine or risperidone found that the risk of developing diabetes was 37% higher in the patients treated with olanzepine. (Medscape).
At current time it appears that the two most recently approved antipsychotics, ziprasadone and aripiprazole, carry the lowest risk for developing diabetes of all the atypical agents (something). Use of quetiapine and risperidone appear to carry a greater risk of diabetes than ziprazpdone or aripiprazole, but less than clozapine and olanzepine. Experience with clozapine and olanzepine is still greater than experience with any of the other atypical agents. Because of this fact it’s reasonable to believe that as time goes on, different conclusions may be reached on the relative propensity to cause diabetes among the atypical antipsychotics.
Weight Gain:
Obesity is a growing epidemic in the United States with almost two-thirds of the population being classified as overweight (BMI > 25 kg/M2), and obesity itself is a well established cause of type 2 diabetes (cdc). There are also well established risk factors that put an individual at an increased risk for being overweight. These risk factors include things like smoking, sedentary lifestyle, and poor diet as a result of lower socio-economic class. In general these risk factors are common among patients with psychiatric illnesses (Sachthansknsa).
Although data is limited, there is some evidence to suggest that the rate of obesity in patients with schizophrenia and affective disorders in medication naïve patients is approximately 1.5-2 times higher than that of the general population. (ADA). There is greater evidence to suggest that treatment with an antipsychotic, whether it is conventional or atypical, results in significant weight gain. Published reports show that as many as 50% of patients will show substantial increases in weight with long term antipsychotic treatment (Sathay). The relative frequency with which weight gain occurs seems to vary with each drug.
Allison, et al preformed a meta-analysis on published reports of changes in weight occurring ten weeks after the initiation of therapy with a neuroleptic. Their findings showed that almost all of the commercially available antipsychotics, regardless of whether they are classified as convetional or atypical agents, cause some degree of weight gain when compared to a placebo. Thioridazine and chlorpromazine were the conventional agents associated with the largest average degree of weight change, at 3.49 kg and 2.10 kg respectively. Among the atypical agents clozapine and olanzepine were shown to have the biggest average increases in weight, at 3.99 kg and 3.51 kg respectively. The conventional agent associated with the least amount of weight gain was molindone which showed on average a 0.81 kg decrease in weight after ten weeks of therapy. The atypical agent that showed the lowest average increase in weight after ten weeks of therapy was ziprasadone, which showed an average increase in weight of only 0.04 kg. (Allison)
In a study by ganguli et al 50 patients on olanzapine were compared with 50 patients on risperidone. Following 4 months or treatment, 36% of the olanzapine group had gained weight in excess of 2 kg of weight, while only 20% of the risperidone group saw levels of weight gain that high.
In a small study conducted by Megna and Dewan average increases in weight were found to be less than 5 kg in patients with schizophrenia who were maintained on risperidone for a period of 16 months. Tendon, et al report average weight gains at one year post initiation of therapy that range from 33 lbs with clozapine, and 25 lbs with olanzapine, to 4-8 lbs with risperidone and quetiapine, to 2 lbs with aripiprazole and ziprazodone.
For now it follows that the relative risk of weight gain associated with the use of atypical antipsychotics appears to be clozapine > olanzapine > quetiapine = risperidone > ziprasodone = aripiprazole. However as time goes on and our experience with the agents increases these assumptions may have to be reevaluated.
Lipids
Hypercholesterolemia and hypertriglyceridemia are also documented risk factors for cardiovascular disease. Increased rates of LDL, total cholesterol and triglycride levels have been reported in patients on antipsychotics.
In the study comparing treatment with haloperidol, clozapine, olanzapine and risperidone, both the clozapine and olanzapine treated groups had a significant increase in total cholesterol eight weeks after therapy was initiatied (lindenamyer). The clozapine group saw an average increase in total cholesterol of 14.7 mg/dL above baseline, while the olanzapine group saw an average increase of 12.3 mg/dl above baseline. There were no significant changes in choleseterol levels in either the haloperidol group or the risperidone group.
A study comparing triglyceride levels after treatment of 222 patients with haloperidol or clozapine showed an association between clozapine use and increased levels of triglycerides in men. Baseline triglyceride levels increased an average of 48.13% in men treated with clozapine. By comparison, men in the study treated with haloperidol showed an average decrease in baseline triglyceride levels of 17.23% after similar period of treatment. Women in both the haloperidol and clozapine groups saw increases in baselign triglyceride levels at an average of 50.51% and 35.38% respectively. (Gaulin)
While the benefits these medications have offered are great, like all medications, the atypical antipsychotics are not without side effects. Just as the atypical agents can be grouped together based on their similar spectrum of symptom coverage and lack of EPS/TD related side effects, they can be grouped together based on their tendency to each cause other similar side effects. Perhaps the most publicized of the side effects that widespread use of these agents has shown are the effects they have had on metabolism, most noteably their tendency
The first medications to treat schizophrenia were introduced in the 1950s. While these early, or “conventional” antipsychotics have been very effective at treating the positive symptoms of the disease, they also tend to cause devastating extrapyramidal motor symptom side effects (EPS) and often irreversible tardive dyskinesia (TD). The symptoms of EPS mimic that of Parkinson’s Disease and include things such as tremor, akathisia, and acute dystonia. TD causes uncontrollable facial and tongue movements like chewing and grimacing and hyperkinetic activity in the distal extremities.
Treatment with pharmaceutical agents like haloperidol, thioridazine, or chlorpromazine control the psychotic aspects of schizophrenia by blocking dopamine type 2 (D2) receptors in the mesolimbic pathway in the brain (402). Unfortunately there are also D2 receptors in other areas of the brain, specifically the substantia nigra and basal ganlia that these agents will block as well which initially cause EPS. With chronic blockade of D2 receptors in the nigrostriatal pathway, EPS will progress to TD at a rate of 4% per year of exposure to the antipsychotic agent.
The development of movement related side effects further increase the social stigma that schizophrenic patients face, making it very difficult to encourage patients to remain compliant with these agents for any length of time. Once patients discontinue treatment psychosis will typically relapse at a rate of approximately 10% per month, so that 50% or more have relapsed by 6 months after the medication is discontinued. (408)
In 1990, clozapine, the first of the new or “atypical” antipsychotics was approved by the FDA for the treatment of schizophrenia. The new agents were given the title of “atypical” because of their similar clinical properties, most noteably their low rates of EPS and efficacy for treating negative symptoms of schizophrenia. Pharmacologically speaking, the medications in this class have chemical structures that are very different from one another, howver they all act on the same receptors in the brain.
Like their conventional counterparts, the atypicals treat the positive symptoms of schizophrenia by blocking D2 receptors. In addition to D2 receptor blockade, the atypicals block serontonin 2A (5HT2A) receptors as well, which helps to explain why these agents are also effective at treating the negative, cognitive, and affective symptoms of schizophrenia. (416)
This antagonism of the 5HT2A receptors in the nigrastriatal pathways of the brain is also thought to be responsible for the relative lack of EPS seen with the atypical agents. 5HT2A antagonism in the nigrostraital pathway leads to the reversal of D2 receptor blockade in the area and blocking 5HT2A receptors also stimulates the release of dopamine in the nigrostriatial pathway. With an increase presence of dopamine in the substansia nigra, the extrapyramidal side effects are virtually eliminated. (417).
As a class, the atypical antipsychotics, have virtually taken over the treatment of schizophrenia, and account for approximately 80% of all antipsychotics prescribed in the United States. (Tandon) There are currently six atypical antipsychotics approved for use in the United States- clozapine (Clozaril), olanzapine (Zyprexa), qutiapine (Seroquel), risperidone (Risperdal), zisprazadone (Geodon), and aripiprazole (Abilify). Clozapine remains the most effect agent available for treating all four dimensions of schizophrenia symptoms. However, it has been associated with agranulocytosis, a rare but life threatening side effect, so its use is reserved for treatment resistant patients.
As experience with the atypical antipsychotics grows, other similarities amongst the different drugs in the class are becoming evident as well. Perhaps the most other most notable similarity with these agents are the metabolic disturbances that often arise in patients that take them. Increased rates of type 2 diabetes, hyperlipidemia, and obesity have all been associated with atypical antipsychotic treatment.
Diabetes:
Type 2 diabetes is a serious health problem in the United States. In 2002 the CDC estimated that approximately 6.3% of the population, or 18.2 million Americans suffer from the disease, and 90% of those have type 2 diabetes (CDC). People with diabetes have a risk of developing heart disease that is 2-4 times greater than that of the general population and diabetes is currently the sixth leading cause of death in the United States (CDC).
Schizophrenia itself appears to carry an increased risk of diabetes unrelated to treatment with antipsychotics. A study of first episode, drug-naïve schizophrenia patients found high rates impaired glucose metabolism, a precursor for the development of type 2 diabetes. Impaired fasting glucose tolerance was observed in 15.4% of the patients with schizophrenia, compared to none of the matched healthy comparison subjects (sas).
Use of antipsychotic medication also appears to increase the risks of developing type 2 diabetes. Rates of diabetes have been found to be higher in patients treated with both typical and atypical antipsychotics than in the general population. A retrospective analysis of more than 56,000 patients treated with antipsychotics (both conventional and atypical) estimated the annual incidence rate of diabetes to be 4.4%, a rate considerably higher than the expected 6.3 cases per 1000 people annually the general U.S. population. (lelise).
The risks may be even greater for younger patients treated with antipsychotic medication. The rate of diabetes for people between the ages of 20-39 in the general U.S. population is 1.1%. Rates of diabetes between 6.2-8.7% were observed in a retrospective analysis of more than 4000 people between the ages of 20-39 who received treatment with a conventional or atypical agent. (sernyak)
There is also evidence available to suggest that the use of atypical agents may be associated with a higher rate of diabetes compared to the use of conventional agents. After controlling for the effects of age, a retrospective comparison of 38,632 patients on antispcychotic therapy: 15,984 on conventional agents and 22,648 on atypical agents, found that paitents who received atypical neuroleptics were 9% more likey to have diabetes than those who receivd conventional agents. (sernyak)
Among the atypical agents, clozapine and olanzapine appear to carry the greatest risk of causing abnormalities in glucose metabolism. At the end of a 5 year study of 82 patients being treated with clozapine, 30 (36.6%) were found to have been diagnosed with type 2 diabetes (Henderson). Another study involving almost 6000 patients using either olanzepine or risperidone found that the risk of developing diabetes was 37% higher in the patients treated with olanzepine. (Medscape).
At current time it appears that the two most recently approved antipsychotics, ziprasadone and aripiprazole, carry the lowest risk for developing diabetes of all the atypical agents (something). Use of quetiapine and risperidone appear to carry a greater risk of diabetes than ziprazpdone or aripiprazole, but less than clozapine and olanzepine. Experience with clozapine and olanzepine is still greater than experience with any of the other atypical agents. Because of this fact it’s reasonable to believe that as time goes on, different conclusions may be reached on the relative propensity to cause diabetes among the atypical antipsychotics.
Weight Gain:
Obesity is a growing epidemic in the United States with almost two-thirds of the population being classified as overweight (BMI > 25 kg/M2), and obesity itself is a well established cause of type 2 diabetes (cdc). There are also well established risk factors that put an individual at an increased risk for being overweight. These risk factors include things like smoking, sedentary lifestyle, and poor diet as a result of lower socio-economic class. In general these risk factors are common among patients with psychiatric illnesses (Sachthansknsa).
Although data is limited, there is some evidence to suggest that the rate of obesity in patients with schizophrenia and affective disorders in medication naïve patients is approximately 1.5-2 times higher than that of the general population. (ADA). There is greater evidence to suggest that treatment with an antipsychotic, whether it is conventional or atypical, results in significant weight gain. Published reports show that as many as 50% of patients will show substantial increases in weight with long term antipsychotic treatment (Sathay). The relative frequency with which weight gain occurs seems to vary with each drug.
Allison, et al preformed a meta-analysis on published reports of changes in weight occurring ten weeks after the initiation of therapy with a neuroleptic. Their findings showed that almost all of the commercially available antipsychotics, regardless of whether they are classified as convetional or atypical agents, cause some degree of weight gain when compared to a placebo. Thioridazine and chlorpromazine were the conventional agents associated with the largest average degree of weight change, at 3.49 kg and 2.10 kg respectively. Among the atypical agents clozapine and olanzepine were shown to have the biggest average increases in weight, at 3.99 kg and 3.51 kg respectively. The conventional agent associated with the least amount of weight gain was molindone which showed on average a 0.81 kg decrease in weight after ten weeks of therapy. The atypical agent that showed the lowest average increase in weight after ten weeks of therapy was ziprasadone, which showed an average increase in weight of only 0.04 kg. (Allison)
In a study by ganguli et al 50 patients on olanzapine were compared with 50 patients on risperidone. Following 4 months or treatment, 36% of the olanzapine group had gained weight in excess of 2 kg of weight, while only 20% of the risperidone group saw levels of weight gain that high.
In a small study conducted by Megna and Dewan average increases in weight were found to be less than 5 kg in patients with schizophrenia who were maintained on risperidone for a period of 16 months. Tendon, et al report average weight gains at one year post initiation of therapy that range from 33 lbs with clozapine, and 25 lbs with olanzapine, to 4-8 lbs with risperidone and quetiapine, to 2 lbs with aripiprazole and ziprazodone.
For now it follows that the relative risk of weight gain associated with the use of atypical antipsychotics appears to be clozapine > olanzapine > quetiapine = risperidone > ziprasodone = aripiprazole. However as time goes on and our experience with the agents increases these assumptions may have to be reevaluated.
Lipids
Hypercholesterolemia and hypertriglyceridemia are also documented risk factors for cardiovascular disease. Increased rates of LDL, total cholesterol and triglycride levels have been reported in patients on antipsychotics.
In the study comparing treatment with haloperidol, clozapine, olanzapine and risperidone, both the clozapine and olanzapine treated groups had a significant increase in total cholesterol eight weeks after therapy was initiatied (lindenamyer). The clozapine group saw an average increase in total cholesterol of 14.7 mg/dL above baseline, while the olanzapine group saw an average increase of 12.3 mg/dl above baseline. There were no significant changes in choleseterol levels in either the haloperidol group or the risperidone group.
A study comparing triglyceride levels after treatment of 222 patients with haloperidol or clozapine showed an association between clozapine use and increased levels of triglycerides in men. Baseline triglyceride levels increased an average of 48.13% in men treated with clozapine. By comparison, men in the study treated with haloperidol showed an average decrease in baseline triglyceride levels of 17.23% after similar period of treatment. Women in both the haloperidol and clozapine groups saw increases in baselign triglyceride levels at an average of 50.51% and 35.38% respectively. (Gaulin)
While the benefits these medications have offered are great, like all medications, the atypical antipsychotics are not without side effects. Just as the atypical agents can be grouped together based on their similar spectrum of symptom coverage and lack of EPS/TD related side effects, they can be grouped together based on their tendency to each cause other similar side effects. Perhaps the most publicized of the side effects that widespread use of these agents has shown are the effects they have had on metabolism, most noteably their tendency
Paper
Schizophrenia remains one of the most severe, chronic, and debilitating psychiatric disorders. Generally beginning in late adolescence or early adulthood, it effects approximately 1% of the population. The disease is characterized by a variety of symptoms along four dimensions: positive symptoms, negative symptoms, cognitive impairments, and disturbances in mood and affect. Life expectancy….
The first medications to treat schizophrenia were introduced in the 1950s. While these early, or “conventional” antipsychotics have been very effective at treating the positive symptoms of the disease, they also tend to cause devastating extrapyramidal motor symptom side effects (EPS) and often irreversible tardive dyskinesia (TD). The symptoms of EPS mimic that of Parkinson’s Disease and include things such as tremor, akathisia, and acute dystonia. TD causes uncontrollable facial and tongue movements like chewing and grimacing and hyperkinetic activity in the distal extremities.
Treatment with pharmaceutical agents like haloperidol, thioridazine, or chlorpromazine control the psychotic aspects of schizophrenia by blocking dopamine type 2 (D2) receptors in the mesolimbic pathway in the brain (402). Unfortunately there are also D2 receptors in other areas of the brain, specifically the substantia nigra and basal ganlia that these agents will block as well which initially cause EPS. With chronic blockade of D2 receptors in the nigrostriatal pathway, EPS will progress to TD at a rate of 4% per year of exposure to the antipsychotic agent.
The development of movement related side effects further increase the social stigma that schizophrenic patients face, making it very difficult to encourage patients to remain compliant with these agents for any length of time. Once patients discontinue treatment psychosis will typically relapse at a rate of approximately 10% per month, so that 50% or more have relapsed by 6 months after the medication is discontinued. (408)
In 1990, clozapine, the first of the new or “atypical” antipsychotics was approved by the FDA for the treatment of schizophrenia. The new agents were given the title of “atypical” because of their similar clinical properties, most noteably their low rates of EPS and efficacy for treating negative symptoms of schizophrenia. Pharmacologically speaking, the medications in this class have chemical structures that are very different from one another, howver they all act on the same receptors in the brain.
Like their conventional counterparts, the atypicals treat the positive symptoms of schizophrenia by blocking D2 receptors. In addition to D2 receptor blockade, the atypicals block serontonin 2A (5HT2A) receptors as well, which helps to explain why these agents are also effective at treating the negative, cognitive, and affective symptoms of schizophrenia. (416)
This antagonism of the 5HT2A receptors in the nigrastriatal pathways of the brain is also thought to be responsible for the relative lack of EPS seen with the atypical agents. 5HT2A antagonism in the nigrostraital pathway leads to the reversal of D2 receptor blockade in the area and blocking 5HT2A receptors also stimulates the release of dopamine in the nigrostriatial pathway. With an increase presence of dopamine in the substansia nigra, the extrapyramidal side effects are virtually eliminated. (417).
As a class, the atypical antipsychotics, have virtually taken over the treatment of schizophrenia, and account for approximately 80% of all antipsychotics prescribed in the United States. (Tandon) There are currently six atypical antipsychotics approved for use in the United States- clozapine (Clozaril), olanzapine (Zyprexa), qutiapine (Seroquel), risperidone (Risperdal), zisprazadone (Geodon), and aripiprazole (Abilify). Clozapine remains the most effect agent available for treating all four dimensions of schizophrenia symptoms. However, it has been associated with agranulocytosis, a rare but life threatening side effect, so its use is reserved for treatment resistant patients.
As experience with the atypical antipsychotics grows, other similarities amongst the different drugs in the class are becoming evident as well. Perhaps the most other most notable similarity with these agents are the metabolic disturbances that often arise in patients that take them. Increased rates of type 2 diabetes, hyperlipidemia, and obesity have all been associated with atypical antipsychotic treatment.
Diabetes:
Type 2 diabetes is a serious health problem in the United States. In 2002 the CDC estimated that approximately 6.3% of the population, or 18.2 million Americans suffer from the disease, and 90% of those have type 2 diabetes (CDC). People with diabetes have a risk of developing heart disease that is 2-4 times greater than that of the general population and diabetes is currently the sixth leading cause of death in the United States (CDC).
Schizophrenia itself appears to carry an increased risk of diabetes unrelated to treatment with antipsychotics. A study of first episode, drug-naïve schizophrenia patients found high rates impaired glucose metabolism, a precursor for the development of type 2 diabetes. Impaired fasting glucose tolerance was observed in 15.4% of the patients with schizophrenia, compared to none of the matched healthy comparison subjects (sas).
Use of antipsychotic medication also appears to increase the risks of developing type 2 diabetes. Rates of diabetes have been found to be higher in patients treated with both typical and atypical antipsychotics than in the general population. A retrospective analysis of more than 56,000 patients treated with antipsychotics (both conventional and atypical) estimated the annual incidence rate of diabetes to be 4.4%, a rate considerably higher than the expected 6.3 cases per 1000 people annually the general U.S. population. (lelise).
The risks may be even greater for younger patients treated with antipsychotic medication. The rate of diabetes for people between the ages of 20-39 in the general U.S. population is 1.1%. Rates of diabetes between 6.2-8.7% were observed in a retrospective analysis of more than 4000 people between the ages of 20-39 who received treatment with a conventional or atypical agent. (sernyak)
There is also evidence available to suggest that the use of atypical agents may be associated with a higher rate of diabetes compared to the use of conventional agents. After controlling for the effects of age, a retrospective comparison of 38,632 patients on antispcychotic therapy: 15,984 on conventional agents and 22,648 on atypical agents, found that paitents who received atypical neuroleptics were 9% more likey to have diabetes than those who receivd conventional agents. (sernyak)
Among the atypical agents, clozapine and olanzapine appear to carry the greatest risk of causing abnormalities in glucose metabolism. At the end of a 5 year study of 82 patients being treated with clozapine, 30 (36.6%) were found to have been diagnosed with type 2 diabetes (Henderson). Another study involving almost 6000 patients using either olanzepine or risperidone found that the risk of developing diabetes was 37% higher in the patients treated with olanzepine. (Medscape).
At current time it appears that the two most recently approved antipsychotics, ziprasadone and aripiprazole, carry the lowest risk for developing diabetes of all the atypical agents (something). Use of quetiapine and risperidone appear to carry a greater risk of diabetes than ziprazpdone or aripiprazole, but less than clozapine and olanzepine. Experience with clozapine and olanzepine is still greater than experience with any of the other atypical agents. Because of this fact it’s reasonable to believe that as time goes on, different conclusions may be reached on the relative propensity to cause diabetes among the atypical antipsychotics.
Weight Gain:
Obesity is a growing epidemic in the United States with almost two-thirds of the population being classified as overweight (BMI > 25 kg/M2), and obesity itself is a well established cause of type 2 diabetes (cdc). There are also well established risk factors that put an individual at an increased risk for being overweight. These risk factors include things like smoking, sedentary lifestyle, and poor diet as a result of lower socio-economic class. In general these risk factors are common among patients with psychiatric illnesses (Sachthansknsa).
Although data is limited, there is some evidence to suggest that the rate of obesity in patients with schizophrenia and affective disorders in medication naïve patients is approximately 1.5-2 times higher than that of the general population. (ADA). There is greater evidence to suggest that treatment with an antipsychotic, whether it is conventional or atypical, results in significant weight gain. Published reports show that as many as 50% of patients will show substantial increases in weight with long term antipsychotic treatment (Sathay). The relative frequency with which weight gain occurs seems to vary with each drug.
Allison, et al preformed a meta-analysis on published reports of changes in weight occurring ten weeks after the initiation of therapy with a neuroleptic. Their findings showed that almost all of the commercially available antipsychotics, regardless of whether they are classified as convetional or atypical agents, cause some degree of weight gain when compared to a placebo. Thioridazine and chlorpromazine were the conventional agents associated with the largest average degree of weight change, at 3.49 kg and 2.10 kg respectively. Among the atypical agents clozapine and olanzepine were shown to have the biggest average increases in weight, at 3.99 kg and 3.51 kg respectively. The conventional agent associated with the least amount of weight gain was molindone which showed on average a 0.81 kg decrease in weight after ten weeks of therapy. The atypical agent that showed the lowest average increase in weight after ten weeks of therapy was ziprasadone, which showed an average increase in weight of only 0.04 kg. (Allison)
In a study by ganguli et al 50 patients on olanzapine were compared with 50 patients on risperidone. Following 4 months or treatment, 36% of the olanzapine group had gained weight in excess of 2 kg of weight, while only 20% of the risperidone group saw levels of weight gain that high.
In a small study conducted by Megna and Dewan average increases in weight were found to be less than 5 kg in patients with schizophrenia who were maintained on risperidone for a period of 16 months. Tendon, et al report average weight gains at one year post initiation of therapy that range from 33 lbs with clozapine, and 25 lbs with olanzapine, to 4-8 lbs with risperidone and quetiapine, to 2 lbs with aripiprazole and ziprazodone.
For now it follows that the relative risk of weight gain associated with the use of atypical antipsychotics appears to be clozapine > olanzapine > quetiapine = risperidone > ziprasodone = aripiprazole. However as time goes on and our experience with the agents increases these assumptions may have to be reevaluated.
Lipids
Hypercholesterolemia and hypertriglyceridemia are also documented risk factors for cardiovascular disease. Increased rates of LDL, total cholesterol and triglycride levels have been reported in patients on antipsychotics.
In the study comparing treatment with haloperidol, clozapine, olanzapine and risperidone, both the clozapine and olanzapine treated groups had a significant increase in total cholesterol eight weeks after therapy was initiatied (lindenamyer). The clozapine group saw an average increase in total cholesterol of 14.7 mg/dL above baseline, while the olanzapine group saw an average increase of 12.3 mg/dl above baseline. There were no significant changes in choleseterol levels in either the haloperidol group or the risperidone group.
A study comparing triglyceride levels after treatment of 222 patients with haloperidol or clozapine showed an association between clozapine use and increased levels of triglycerides in men. Baseline triglyceride levels increased an average of 48.13% in men treated with clozapine. By comparison, men in the study treated with haloperidol showed an average decrease in baseline triglyceride levels of 17.23% after similar period of treatment. Women in both the haloperidol and clozapine groups saw increases in baselign triglyceride levels at an average of 50.51% and 35.38% respectively. (Gaulin)
While the benefits these medications have offered are great, like all medications, the atypical antipsychotics are not without side effects. Just as the atypical agents can be grouped together based on their similar spectrum of symptom coverage and lack of EPS/TD related side effects, they can be grouped together based on their tendency to each cause other similar side effects. Perhaps the most publicized of the side effects that widespread use of these agents has shown are the effects they have had on metabolism, most noteably their tendency
The first medications to treat schizophrenia were introduced in the 1950s. While these early, or “conventional” antipsychotics have been very effective at treating the positive symptoms of the disease, they also tend to cause devastating extrapyramidal motor symptom side effects (EPS) and often irreversible tardive dyskinesia (TD). The symptoms of EPS mimic that of Parkinson’s Disease and include things such as tremor, akathisia, and acute dystonia. TD causes uncontrollable facial and tongue movements like chewing and grimacing and hyperkinetic activity in the distal extremities.
Treatment with pharmaceutical agents like haloperidol, thioridazine, or chlorpromazine control the psychotic aspects of schizophrenia by blocking dopamine type 2 (D2) receptors in the mesolimbic pathway in the brain (402). Unfortunately there are also D2 receptors in other areas of the brain, specifically the substantia nigra and basal ganlia that these agents will block as well which initially cause EPS. With chronic blockade of D2 receptors in the nigrostriatal pathway, EPS will progress to TD at a rate of 4% per year of exposure to the antipsychotic agent.
The development of movement related side effects further increase the social stigma that schizophrenic patients face, making it very difficult to encourage patients to remain compliant with these agents for any length of time. Once patients discontinue treatment psychosis will typically relapse at a rate of approximately 10% per month, so that 50% or more have relapsed by 6 months after the medication is discontinued. (408)
In 1990, clozapine, the first of the new or “atypical” antipsychotics was approved by the FDA for the treatment of schizophrenia. The new agents were given the title of “atypical” because of their similar clinical properties, most noteably their low rates of EPS and efficacy for treating negative symptoms of schizophrenia. Pharmacologically speaking, the medications in this class have chemical structures that are very different from one another, howver they all act on the same receptors in the brain.
Like their conventional counterparts, the atypicals treat the positive symptoms of schizophrenia by blocking D2 receptors. In addition to D2 receptor blockade, the atypicals block serontonin 2A (5HT2A) receptors as well, which helps to explain why these agents are also effective at treating the negative, cognitive, and affective symptoms of schizophrenia. (416)
This antagonism of the 5HT2A receptors in the nigrastriatal pathways of the brain is also thought to be responsible for the relative lack of EPS seen with the atypical agents. 5HT2A antagonism in the nigrostraital pathway leads to the reversal of D2 receptor blockade in the area and blocking 5HT2A receptors also stimulates the release of dopamine in the nigrostriatial pathway. With an increase presence of dopamine in the substansia nigra, the extrapyramidal side effects are virtually eliminated. (417).
As a class, the atypical antipsychotics, have virtually taken over the treatment of schizophrenia, and account for approximately 80% of all antipsychotics prescribed in the United States. (Tandon) There are currently six atypical antipsychotics approved for use in the United States- clozapine (Clozaril), olanzapine (Zyprexa), qutiapine (Seroquel), risperidone (Risperdal), zisprazadone (Geodon), and aripiprazole (Abilify). Clozapine remains the most effect agent available for treating all four dimensions of schizophrenia symptoms. However, it has been associated with agranulocytosis, a rare but life threatening side effect, so its use is reserved for treatment resistant patients.
As experience with the atypical antipsychotics grows, other similarities amongst the different drugs in the class are becoming evident as well. Perhaps the most other most notable similarity with these agents are the metabolic disturbances that often arise in patients that take them. Increased rates of type 2 diabetes, hyperlipidemia, and obesity have all been associated with atypical antipsychotic treatment.
Diabetes:
Type 2 diabetes is a serious health problem in the United States. In 2002 the CDC estimated that approximately 6.3% of the population, or 18.2 million Americans suffer from the disease, and 90% of those have type 2 diabetes (CDC). People with diabetes have a risk of developing heart disease that is 2-4 times greater than that of the general population and diabetes is currently the sixth leading cause of death in the United States (CDC).
Schizophrenia itself appears to carry an increased risk of diabetes unrelated to treatment with antipsychotics. A study of first episode, drug-naïve schizophrenia patients found high rates impaired glucose metabolism, a precursor for the development of type 2 diabetes. Impaired fasting glucose tolerance was observed in 15.4% of the patients with schizophrenia, compared to none of the matched healthy comparison subjects (sas).
Use of antipsychotic medication also appears to increase the risks of developing type 2 diabetes. Rates of diabetes have been found to be higher in patients treated with both typical and atypical antipsychotics than in the general population. A retrospective analysis of more than 56,000 patients treated with antipsychotics (both conventional and atypical) estimated the annual incidence rate of diabetes to be 4.4%, a rate considerably higher than the expected 6.3 cases per 1000 people annually the general U.S. population. (lelise).
The risks may be even greater for younger patients treated with antipsychotic medication. The rate of diabetes for people between the ages of 20-39 in the general U.S. population is 1.1%. Rates of diabetes between 6.2-8.7% were observed in a retrospective analysis of more than 4000 people between the ages of 20-39 who received treatment with a conventional or atypical agent. (sernyak)
There is also evidence available to suggest that the use of atypical agents may be associated with a higher rate of diabetes compared to the use of conventional agents. After controlling for the effects of age, a retrospective comparison of 38,632 patients on antispcychotic therapy: 15,984 on conventional agents and 22,648 on atypical agents, found that paitents who received atypical neuroleptics were 9% more likey to have diabetes than those who receivd conventional agents. (sernyak)
Among the atypical agents, clozapine and olanzapine appear to carry the greatest risk of causing abnormalities in glucose metabolism. At the end of a 5 year study of 82 patients being treated with clozapine, 30 (36.6%) were found to have been diagnosed with type 2 diabetes (Henderson). Another study involving almost 6000 patients using either olanzepine or risperidone found that the risk of developing diabetes was 37% higher in the patients treated with olanzepine. (Medscape).
At current time it appears that the two most recently approved antipsychotics, ziprasadone and aripiprazole, carry the lowest risk for developing diabetes of all the atypical agents (something). Use of quetiapine and risperidone appear to carry a greater risk of diabetes than ziprazpdone or aripiprazole, but less than clozapine and olanzepine. Experience with clozapine and olanzepine is still greater than experience with any of the other atypical agents. Because of this fact it’s reasonable to believe that as time goes on, different conclusions may be reached on the relative propensity to cause diabetes among the atypical antipsychotics.
Weight Gain:
Obesity is a growing epidemic in the United States with almost two-thirds of the population being classified as overweight (BMI > 25 kg/M2), and obesity itself is a well established cause of type 2 diabetes (cdc). There are also well established risk factors that put an individual at an increased risk for being overweight. These risk factors include things like smoking, sedentary lifestyle, and poor diet as a result of lower socio-economic class. In general these risk factors are common among patients with psychiatric illnesses (Sachthansknsa).
Although data is limited, there is some evidence to suggest that the rate of obesity in patients with schizophrenia and affective disorders in medication naïve patients is approximately 1.5-2 times higher than that of the general population. (ADA). There is greater evidence to suggest that treatment with an antipsychotic, whether it is conventional or atypical, results in significant weight gain. Published reports show that as many as 50% of patients will show substantial increases in weight with long term antipsychotic treatment (Sathay). The relative frequency with which weight gain occurs seems to vary with each drug.
Allison, et al preformed a meta-analysis on published reports of changes in weight occurring ten weeks after the initiation of therapy with a neuroleptic. Their findings showed that almost all of the commercially available antipsychotics, regardless of whether they are classified as convetional or atypical agents, cause some degree of weight gain when compared to a placebo. Thioridazine and chlorpromazine were the conventional agents associated with the largest average degree of weight change, at 3.49 kg and 2.10 kg respectively. Among the atypical agents clozapine and olanzepine were shown to have the biggest average increases in weight, at 3.99 kg and 3.51 kg respectively. The conventional agent associated with the least amount of weight gain was molindone which showed on average a 0.81 kg decrease in weight after ten weeks of therapy. The atypical agent that showed the lowest average increase in weight after ten weeks of therapy was ziprasadone, which showed an average increase in weight of only 0.04 kg. (Allison)
In a study by ganguli et al 50 patients on olanzapine were compared with 50 patients on risperidone. Following 4 months or treatment, 36% of the olanzapine group had gained weight in excess of 2 kg of weight, while only 20% of the risperidone group saw levels of weight gain that high.
In a small study conducted by Megna and Dewan average increases in weight were found to be less than 5 kg in patients with schizophrenia who were maintained on risperidone for a period of 16 months. Tendon, et al report average weight gains at one year post initiation of therapy that range from 33 lbs with clozapine, and 25 lbs with olanzapine, to 4-8 lbs with risperidone and quetiapine, to 2 lbs with aripiprazole and ziprazodone.
For now it follows that the relative risk of weight gain associated with the use of atypical antipsychotics appears to be clozapine > olanzapine > quetiapine = risperidone > ziprasodone = aripiprazole. However as time goes on and our experience with the agents increases these assumptions may have to be reevaluated.
Lipids
Hypercholesterolemia and hypertriglyceridemia are also documented risk factors for cardiovascular disease. Increased rates of LDL, total cholesterol and triglycride levels have been reported in patients on antipsychotics.
In the study comparing treatment with haloperidol, clozapine, olanzapine and risperidone, both the clozapine and olanzapine treated groups had a significant increase in total cholesterol eight weeks after therapy was initiatied (lindenamyer). The clozapine group saw an average increase in total cholesterol of 14.7 mg/dL above baseline, while the olanzapine group saw an average increase of 12.3 mg/dl above baseline. There were no significant changes in choleseterol levels in either the haloperidol group or the risperidone group.
A study comparing triglyceride levels after treatment of 222 patients with haloperidol or clozapine showed an association between clozapine use and increased levels of triglycerides in men. Baseline triglyceride levels increased an average of 48.13% in men treated with clozapine. By comparison, men in the study treated with haloperidol showed an average decrease in baseline triglyceride levels of 17.23% after similar period of treatment. Women in both the haloperidol and clozapine groups saw increases in baselign triglyceride levels at an average of 50.51% and 35.38% respectively. (Gaulin)
While the benefits these medications have offered are great, like all medications, the atypical antipsychotics are not without side effects. Just as the atypical agents can be grouped together based on their similar spectrum of symptom coverage and lack of EPS/TD related side effects, they can be grouped together based on their tendency to each cause other similar side effects. Perhaps the most publicized of the side effects that widespread use of these agents has shown are the effects they have had on metabolism, most noteably their tendency
Friday, March 11, 2005
Atypical Antipsychotics
Schizophrenia remains one of the most severe, chronic, and debilitating psychiatric disorders. It generally begins in late adolescence or early adulthood and effects approximately 1% of the population. The disease is characterized by a variety of symptoms along four dimensions: positive symptoms, negative symptoms, cognitive impairments, and disturbances in mood and affect.
The first medications to treat schizophrenia were introduced in the 1950s. While these early, or “conventional” antipsychotics are very effective at treating the positive symptoms of the disease, they also tend to cause devastating, and often irreversible extrapyramidal side effects.
The first medications to treat schizophrenia were introduced in the 1950s. While these early, or “conventional” antipsychotics are very effective at treating the positive symptoms of the disease, they also tend to cause devastating, and often irreversible extrapyramidal side effects.
