Answer. I appreciate how confusing some of these medication issues can be for parents and families of individuals with schizophrenia. Terms like “older” and “newer” can be confusing when applied to medications for psychosis or mood. For example, how “new” or “old” an antipsychotic is has more to do with marketing and approval processes than with how effective or safe it is.

Generally speaking, clinicians distinguish two broad groups of antipsychotic agents: older “typical” agents, also called neuroleptics, and the newer “atypical” agents. The latter group includes clozapine (Clozaril), the first atypical released; risperidone (Risperdal), which came out next; and then olanzapine (Zyprexa) and quetiapine (Seroquel). As a group, the atypicals are generally more effective for so-called negative symptoms of schizophrenia (apathy, social withdrawal), and are less likely to cause neuro-muscular problems like muscle spasms, stiffness, and abnormal movements (tardive dyskinesia).

However, the atypical agents are not without side effects. On rare occasion clozapine can cause a serious white blood cell problem called agranulocytosis, and it does tend to promote significant weight gain. On the other hand, many clinicians believe clozapine to be the most effective agent, old or new, for severe, refractory schizophrenia. Several studies do suggest clozapine is somewhat more effective than risperidone, though risperidone tends to have fewer side effects (such as weight gain). Olanzapine, as you note, is closely related to clozapine, but it is not yet known if it is as effective. Though olanzapine is generally better tolerated than clozapine and does not cause the white blood cell problem, it can also contribute to weight gain.

Regarding your son, many clinicians would argue that a failure to respond well to risperidone justifies a direct move to “the gold standard,” clozapine. Others (probably including me) might give olanzapine a try first, then go to clozapine. But this isn’t a matter of old vs. new as much as a matter of balancing risks and benefits on a case-by-case basis. The same applies to Paxil (which, compared to many agents on the market, is actually quite “new”). By the way, sometimes the older agents (such as haloperidol) are used to augment newer agents, as seems to be the case with your son.

To summarize, the changes in medication you have described aren’t “wrong,” but your son’s response is hard to predict. Clozapine certainly gives him a very good chance of recovery. The other atypical agent now available, quetiapine, has not really been compared in good studies with clozapine; my own impression is that quetiapine is a useful agent, but “no clozapine.” We are expecting yet another atypical agent, ziprasidone, in the next 6-10 months, and this agent appears to cause little if any weight gain. It may also have antidepressant properties, and could be useful for your son. But it’s not at all clear that it will out-perform clozapine.

Making Seroquel tablets work for you

• Seroquel is available as tablets you take by mouth. You should take Seroquel tablets every day or as your doctor has directed. To gain the most benefits from Seroquel tablets, take the exact number of tablets your doctor has prescribed for you each day at the appropriate times. Regardless of how good or how bad you feel, do not stop taking Seroquel tablets without notifying your doctor.
• If you miss a dose, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and return to your regular dosing schedule. Do not take two doses at once. If you are unsure, speak with your doctor.
• During therapy with Seroquel tablets, especially during the initial dosing period, you may experience light-headedness or dizziness, especially when standing up quickly or getting out of bed. To help prevent this feeling, rise slowly from your chair or bed.
• Drowsiness can be a side-effect of Seroquel tablets especially during the first 3-5 days after you begin taking Seroquel tablets. Use caution when performing any activity requiring alertness, including operating an automobile or other hazardous machinery, until you are reasonably certain Seroquel tablets do not cause you to be drowsy.
• You should avoid drinking alcoholic beverages while taking Seroquel tablets.
• Avoid becoming overheated or dehydrated while you are taking Seroquel tablets.
• It is very important to take your doses of Seroquel tablets every day or as your doctor recommends, even once your symptoms go away and as you’re feeling better.
• Seroquel tablets may be taken with or without food.

Consulting with your doctor and pharmacist

• Keep your doctor informed of how you are feeling on Seroquel tablets.
• Discuss any side-effects or other symptoms you are experiencing or questions you have regarding your treatment with Seroquel tablets.
• Ask about scheduling periodic eye exams.
• Talk to your doctor and pharmacist about any other prescription or nonprescription drugs you are currently taking, since certain medications may affect the way they work.
• Notify your doctor if you are pregnant or plan on becoming pregnant while taking Seroquel tablets.
• Tell your doctor if you are planning to breast-feed – You should not breast-feed while taking Seroquel tablets.
• You should call your doctor right away if you have any questions or concerns about your symptoms, treatment, or how you are feeling in general.
• Remember to take your Seroquel tablets every day as directed, and do NOT stop taking Seroquel tablets without notifying your doctor. Seroquel tablets, when taken as directed, can help you achieve a more normal life.

Clinical data recently presented at a major US psychiatric conference suggest that Seroquel ® (Quetiapine Fumarate) Tablets continue to be safe, effective and well-tolerated in the long-term treatment of both positive and negative symptoms of schizophrenia in adults.

Positive and negative symptoms of schizophrenia

Major features of schizophrenia include positive symptoms such as delusions, and hallucinations, and negative symptoms such as apathy, depression, and social withdrawal. While older antipsychotic medications have frequently been used to relieve the positive symptoms of schizophrenia, the newer class of atypical antipsychotic medications including Seroquel, have been shown to be effective in controlling both the negative and positive symptoms.

“Approximately one in every 100 people develops schizophrenia. This psychiatric disorder occurs worldwide despite a person’s gender, culture, ethnicity and religion,” said Jonathan Hellewell, Department of Psychiatry, Trafford General Hospital, Manchester, United Kingdom and lead author of one of the studies. “Typically, schizophrenia is a lifelong illness with symptoms that change in severity over time. It is therefore critical to maintain treatment for a long period of time.”

Assessment of long-term efficacy with Seroquel

Results from one analysis suggest that, among adult patients with schizophrenia and elderly patients with psychosis who showed an initial response to Seroquel treatment, the medication offers maintained response for both positive and negative symptoms of schizophrenia over the long-term.

Results were gleaned from data collected from 52-week, open label extension (OLE) trials of three studies in adults (n=267), and one study of elderly patients (n=184). Patients who had a meaningful clinical response to Seroquel in the acute phase were eligible for the OLE phase.3 Response was defined as 40 percent reduction in Brief Psychiatric Rating Scale (BPRS) total score from baseline or a BPRS total score of 18 points at week six.

In the three OLE studies, improvements in symptoms were maintained over 52-week study period as measured by each assessment scale utilized in the study. (BPRS 14.0 vs. 12.7; CGI Severity Illness 3.0 vs. 2.8; BPRS Positive Symptom Cluster score 1.3 vs. 1.0; and Scale for Assessment of Negative Symptoms 9.5 vs. 8.2) The analysis of the elderly patients also suggested that the efficacy of Seroquel was maintained during the treatment period.

Seroquel (quetiapine fumarate) continued to be well tolerated throughout the OLE treatment period. No new safety issues were identified in adult patients. Safety in elderly patients was confirmed by the low rate of withdrawal for adverse events (15%).

The most common adverse events associated with the use of Seroquel are dizziness (10%), postural hypotension (7%), dry mouth (7%) and dyspepsia (6%) and the majority of events are rated mild or moderate.

Assessment of long-term efficacy and safety of Seroquel in the treatment of schizophrenia

Results of a second analysis were gathered from data collected from four open label extension (OLE) studies in which 674 patients with schizophrenia (65.6 percent male), with a mean age of 36.4 years received Seroquel for up to 130 weeks. Various assessment scales i for mental illness were used to measure the long-term efficacy and tolerability of Seroquel. Each measurement suggested a continued improvement in efficacy up to the end of the study. Study results indicated Seroquel was well-tolerated during long-term therapy with significant improvements from baseline observed at 13, 26, 52, 65, 78, 91, 104 and 130 weeks.

“We were pleased to see that Seroquel continues to maintain its effectiveness for treatment of both the positive and negative symptoms of schizophrenia for patients who require long-term treatment,” said Siegfried Kasper, M.D., Professor of Psychiatry and Chairman of the Department of General Psychiatry at the University of Vienna, Austria, and lead author of the study. “With medications such as Seroquel (quetiapine fumarate), patients suffering from schizophrenia may now continue taking an effective medication that has been shown to improve their symptoms for an extended period of time.”

The effectiveness of Seroquel in long-term use, that is, for more than six weeks, has not been systematically evaluated in controlled trials.

Safety during long-term exposure to Seroquel

Data from a third analysis evaluated the long-term safety of Seroquel for patients treated for up to three years during the open-label extension (OLE) phases of the Seroquel Phase IIIb clinical trial program. A total of 478 patients with a mean age of 39 years who were diagnosed with schizophrenia or schizoaffective disorder were included in the assessment.

The median duration of exposure to Seroquel was 30 weeks. Mean daily doses during OLE treatment averaged between 450-500 mg throughout the three year period. Adverse-event profile during open-label treatment was similar to that observed during the randomized periods of the individual trials, no safety concerns were raised.

• Seroquel belongs to a new chemical class of atypical antipsychotics known as dibenzothiazepine derivatives.

• Three, short-term (six weeks or less) controlled trials of psychotic patients demonstrated that Seroquel is effective in treating both the positive and negative symptoms associated with schizophrenia.

Additionally, the incidence of extrapyramidal symptoms (EPS) with Seroquel was no different from placebo across the clinical dose range. Elevations in plasma prolactin levels among study participants in the Seroquel groups were no different from the placebo-treated groups across the clinical dose range.

• Studies showed Seroquel to exhibit a low incidence of anticholinergic side effects (i.e., dry mouth, constipation) and no blood monitoring is required.

• Seroquel is manufactured in the US and is currently available by prescription throughout the US in strengths of 25 mg, 100 mg, and 200 mg tablets.

In one clinical trial, efficacy was demonstrated in a dose range of 150 mg/day to 750 mg/day. An initial target dose range of 300 – 400 mg can be given in two divided doses daily. In other studies, doses in the range of 400 – 400 mg/day were effective. A dosing regimen of two to three times daily is recommended.

• The labeling for Seroquel (like other agents in its class) includes a warning relative to a rare condition known as tardive dyskinesia, a condition often associated with long term use of antipsychotic agents, and neuroleptic malignant syndrome (NMS). Symptoms of NMS include muscle rigidity or irregular pulse.

• Label precautions for Seroquel include orthostatic hypotension (dizziness) and tachycardia (fast heartbeat). Also included is a precaution for seizures. As with other antipsychotics, Seroquel should be used cautiously in patients with a history of seizures or with conditions that can potentially lower the seizure threshold.

• The most common adverse events exhibited across placebo-controlled trials included somnolence (18%), headache (19%), and dizziness (10%), and the majority of events rated as mild or moderate.

• The safety and effectiveness of Seroquel in pediatric patients less than 18 years of age has not been established.

• Prior to the introduction of Seroquel, medications used to treat schizophrenia include older, first-generation, "typical" agents (haloperidol) and newer, atypical antipsychotics (clozapine, olanzapine, risperidone).

• Seroquel was discovered and developed by Zeneca Pharmaceuticals, a business unit of Zeneca Inc., in its US research laboratories in Wilmington, DE. Zeneca submitted a New Drug Application (NDA) with the FDA for Seroquel tablets on July 29, 1996.