- Ziprasidone (Geodon®, Zeldox®)
- What is ziprasidone used for?
- How does ziprasidone work?
- Ziprasidone in children and adolescents
- How should ziprasidone be taken?
- When will ziprasidone start working?
- How long do I have to take ziprasidone?
- Is ziprasidone addictive?
- What are the side effects of ziprasidone and what should I do if I get them?
- What precautions should my doctor and I be aware of when taking ziprasidone?
- What special instructions should I follow while using ziprasidone?
- What should I do if I forget to take a dose of ziprasidone?
- Share this document
- About this document
- Creative Commons license
- ziprasidone (Rx)
- Ziprasidone Augmentation May Have Benefits in Depression
- Ziprasidone as Adjunctive Therapy in Severe Bipolar Patients Treated with Clozapine
- 1. Introduction
- 2. Material and Methods
- 3. Results
- 4. Supplementary Data
- 5. Discussion
- 6. Study Limitations
- Conflict of Interests
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Ziprasidone (Geodon®, Zeldox®)
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What is ziprasidone used for?
Ziprasidone is used in various conditions including:
- Schizophrenia and other thought disorders
- Symptoms associated with autism
- Bipolar disorder
- Tourette syndrome
Your doctor may be using this medication for another reason. If you are unclear why this medication is being prescribed, please ask your doctor.
How does ziprasidone work?
Like other atypical antipsychotics, ziprasidone affects the levels of certain chemicals in the brain called dopamine and serotonin. This has been shown to help people who have disorders like schizophrenia and bipolar disorder with their symptoms.
Ziprasidone in children and adolescents
Like many medications used to treat childhood disorders, ziprasidone has not been approved by Health Canada for use in children and adolescents.
Nonetheless, current evidence supports the use of ziprasidone in children and adolescents. Ziprasidone has been shown in a study to be better than placebo (an inactive pill that looks like the medication) for treating bipolar disorder and Tourette syndrome in children and adolescents. Although the majority of information for the use of ziprasidone in schizophrenia is from trials done in adults, more trials in children and adolescents are currently underway.
Thus, when the potential benefits (e.g., reducing symptoms) of using ziprasidone outweigh the potential risks (e.g., the side effects), many doctors may prescribe it “off-label” in children and adolescents.
How should ziprasidone be taken?
Ziprasidone is available as a capsule that is usually taken twice daily. It should be taken with food to improve absorption. This medication should be taken at the same times each day as directed by your doctor. Try to connect taking it with something you do each day (like eating breakfast, or brushing your teeth) so that you don’t forget. Try to avoid alcohol while taking ziprasidone.
Usually, your doctor will start with a low dose of ziprasidone that is best suited to your age and weight. The dose will then be slowly increased over a few weeks based on how you respond. You and your doctor can then discuss the best dosage to stay on based on how you tolerate this medication (how well it helps decrease your symptoms and how you are doing with side effects).
When will ziprasidone start working?
This depends on what you are using it for. Some improvements may be seen in as little as 1 to 2 weeks. However, it can sometimes take up to 6 weeks to see the full benefits of the medication. When ziprasidone is working well, you may notice that your thoughts are clearer and more organized. Agitation may be decreased and hearing voices or seeing things no one else sees (hallucinations) may stop completely or happen much less. Your mood may be more settled and you may see a reduction of intense fears and worries. It is important that you continue taking ziprasidone regularly even if you are feeling well, as it can prevent symptoms from returning. If you are taking this medication to help with symptoms of mood disturbance, you may notice some changes in the first 1 to 2 weeks.
Medications like ziprasidone do not work for everyone. If you are not feeling better within 6 weeks, your doctor may recommend switching you to a different medication.
How long do I have to take ziprasidone?
This depends on the symptoms you have, how frequently they occur, and how long you have had them. Most people will need to take ziprasidone for several months. This allows time for your symptoms to stabilize and for you to regain your functioning. Your doctor will discuss the benefits and risks of taking ziprasidone with you. At this time, you can also discuss how long you might need to take this medication.
Do not increase, decrease, or stop taking this medication without discussing it with your doctor. If you stop taking ziprasidone suddenly, it is possible that your symptoms may return or you may have a bad reaction.
Is ziprasidone addictive?
No, ziprasidone is not addictive and you will not have “cravings” for this medication like you might with nicotine or street drugs. If you and your doctor decide it is best for you to stop taking ziprasidone, your doctor will explain how to safely come off this medication so you don’t feel negative effects as your body adjusts to being without it.
What are the side effects of ziprasidone and what should I do if I get them?
As with most medications, side effects may occur when taking ziprasidone. However, most side effects are mild and temporary. Sometimes the side effects may occur before any of the beneficial effects. It is also possible for some individuals to experience side effects that they feel are concerning or long-lasting. If this occurs, speak to your doctor about ways to manage them. Below are some of the more common side effects of taking this medicine. In brackets are suggested ways to lessen these effects.
Common side effects
Side effects are usually more common when starting a medication or after a dose increase. If any of these side effects is troublesome for you, please discuss them with your doctor, nurse or pharmacist.
- Agitation, anxiety or restlessness (avoid caffeine from energy drinks, colas and coffee)
- Blurred vision (this effect often becomes less noticeable over time)
- Constipation (increase exercise, fluids, vegetables, fruits and fiber)
- Dizziness (try getting up slowly from a sitting or lying down position)
- Dry mouth (try chewing sugarless gum, sour candies, ice chips, or popsicles)
- Headache (try using a pain reliever like acetaminophen (plain Tylenol®))
- Increase in hunger (avoid high calorie foods)
- Nausea, upset stomach, poor appetite (try taking the medication with food)
- Stomach ache (try taking the medication with food)
- Tiredness, drowsiness, or difficulty falling asleep (speak with your doctor if these effects persist)
- Weight gain (monitor your food intake, increase your exercise)
Uncommon side effects (e.g., those that occur in less than 5% of patients)
Contact your doctor IMMEDIATELY if you have any of these side effects:
- Fainting, feeling lightheaded or difficulties with balance
- Fast or irregular heart beat
- Feelings of restlessness
- Fever or excessive sweating
- Frequent urination accompanied by excessive thirst
- Shaking, stiffness or difficulty moving, muscle spasm or stiffness in your throat or tongue
- Thoughts of hurting yourself, suicide, increased irritability/hostility or feeling worse
- Weakness or severe muscle pain
Ziprasidone is sometimes associated with a very rare side effect called “neuroleptic malignant syndrome”. The symptoms may include severe muscle stiffness, high fever, increased heart rate and blood pressure, irregular heartbeat (pulse) and sweating. Contact your doctor right away if this occurs.
On rare occasions, medications like ziprasidone have been associated with a side effect called “tardive dyskinesia”. This is a side effect that can sometimes become permanent in patients who take antipsychotic medications. It involves involuntary movements of some muscles in the body like the lips, tongue, toes, hands and neck. Stopping the antipsychotic at the first signs of it occurring or switching to another “atypical” antipsychotic can decrease the chances of having this side effect continue.
Tip: Ziprasidone can make some individuals feel drowsy, dizzy, or slowed down. If you experience these temporary side effects, it is important to avoid operating heavy machinery or driving a car.
What precautions should my doctor and I be aware of when taking ziprasidone?
Tell your doctor or pharmacist if you:
- Have any allergies, or have experienced a reaction to a medication.
- Are lactose intolerant (ziprasidone capsules contain lactose).
- Are taking, or plan to start taking any other prescription or non-prescription medications (including herbal products). Some medications may interact with ziprasidone and should not be taken with ziprasidone. Your doctor may need to change the medications, the doses of your medications, or monitor you carefully for side effects if you are taking medications that interact with ziprasidone.
- Have a history of low blood pressure, diabetes, kidney disease, blood or bone marrow problems, seizures, or a personal or family history of a heart condition.
- Miss a period, are pregnant (or planning to become pregnant) or are breast-feeding.
- Are currently using alcohol or street drugs. These substances may interfere with how well ziprasidone works for you and/or make you feel drowsy.
Tip: When taking this medication, your body may have difficulty regulating your temperature. Make sure you drink lots of fluids or water to avoid becoming dehydrated. You should avoid doing a lot of physical activities on hot days.
What special instructions should I follow while using ziprasidone?
- Keep all appointments with your doctor and the laboratory. Your doctor may order certain lab tests to check how you are responding to ziprasidone, and to monitor for side effects.
- Do not allow anyone else to use your medication.
What should I do if I forget to take a dose of ziprasidone?
If you take ziprasidone regularly and you forget to take it, take the missed dose as soon as you remember. However, if it is almost time for your next dose (e.g. within 4 hours), skip the missed dose and continue with your regular dosing schedule. Do NOT double your next dose.
What storage conditions are needed for ziprasidone?
- Keep this medication in the original container, stored at room temperature away from
- moisture and heat (e.g. not in the bathroom or kitchen) and protected from light.
- Keep this medication out of reach and sight of children
You may wish to share this information with your family members to help them to understand your treatment options. Since every person’s needs are different, it is important that you follow the advice provided to you by your own doctor, nurse and/or pharmacist and speak to them if you have any questions about this medication.
About this document
Special thanks to the Kelty Centre for Mental Health for permission to adapt this document. The original document was developed by health professionals of BC Mental Health and Addiction Services, and reviewed by the staff of the Kelty Mental Health Centre. French translation provided courtesy of the Ontario Centre of Excellence for Child and Youth Mental Health and the Children’s Hospital of Eastern Ontario (CHEO).
Creative Commons license
You are free to copy and distribute this material unchanged and in its entirety as long as 1) this material is not used in any way that suggests we endorse you or your use of the material, 2) this material is not used for commercial purposes (non-commercial), 3) this material is not altered in any way (no derivative works). View full license at http://creativecommons.org/licenses/by-nc-nd/2.5/ca/. For any other uses, please contact the original rights holder, the Kelty Mental Health Centre.
Information in this pamphlet is offered ‘as is’ and is meant only to provide general information that supplements, but does not replace the information from your health provider. Always contact a qualified health professional for further information in your specific situation or circumstance.
Before taking ziprasidone, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.
Before using this medication, tell your doctor or pharmacist your medical history, especially of: dementia, seizures, low white blood cell count, difficulty swallowing, heart disease (such as coronary artery disease, irregular heartbeat), diabetes (including family history), obesity, breathing trouble during sleep (sleep apnea).
Ziprasidone may cause a condition that affects the heart rhythm (QT prolongation). QT prolongation can rarely cause serious (rarely fatal) fast/irregular heartbeat and other symptoms (such as severe dizziness, fainting) that need medical attention right away.
The risk of QT prolongation may be increased if you have certain medical conditions or are taking other drugs that may cause QT prolongation. Before using ziprasidone, tell your doctor or pharmacist of all the drugs you take and if you have any of the following conditions: certain heart problems (heart failure, recent heart attack, slow heartbeat, QT prolongation in the EKG), family history of certain heart problems (QT prolongation in the EKG, sudden cardiac death).
Low levels of potassium or magnesium in the blood may also increase your risk of QT prolongation. This risk may increase if you use certain drugs (such as diuretics/”water pills”) or if you have conditions such as severe sweating, diarrhea, or vomiting. Talk to your doctor about using ziprasidone safely.
This drug may make you dizzy or drowsy. Alcohol or marijuana (cannabis) can make you more dizzy or drowsy. Do not drive, use machinery, or do anything that needs alertness until you can do it safely. Avoid alcoholic beverages. Talk to your doctor if you are using marijuana (cannabis).
Before having surgery, tell your doctor or dentist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products).
This medication may make you sweat less, making you more likely to get heat stroke. Avoid doing things that may cause you to overheat, such as hard work or exercise in hot weather, or using hot tubs. When the weather is hot, drink a lot of fluids and dress lightly. If you overheat, quickly look for a place to cool down and rest. Get medical help right away if you have a fever that does not go away, mental/mood changes, headache, or dizziness.
Older adults may be more sensitive to the side effects of this drug, especially drowsiness, dizziness, lightheadedness, uncontrolled movements, and QT prolongation (see above). Drowsiness, dizziness, and lightheadedness can increase the risk of falling.
During pregnancy, this medication should be used only when clearly needed. Babies born to mothers who have used this drug during the last 3 months of pregnancy may rarely develop symptoms including muscle stiffness or shakiness, drowsiness, feeding/breathing difficulties, or constant crying. If you notice any of these symptoms in your newborn especially during their first month, tell the doctor right away.
Since untreated mental/mood problems (such as schizophrenia, bipolar disorder, depression) can be a serious condition, do not stop taking this medication unless directed by your doctor. If you are planning pregnancy, become pregnant, or think you may be pregnant, immediately discuss with your doctor the benefits and risks of using this medication during pregnancy.
It is unknown if this drug passes into breast milk. Because of the possible risk to the infant, breast-feeding while using this drug is not recommended. Consult your doctor before breast-feeding.
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Black Box Warnings
Not approved for dementia-related psychosis; patients with dementia-related psychosis who are treated with antipsychotic drugs are at increased risk of death, as shown in short-term controlled trials; deaths in these trials appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature
Not approved for the treatment of dementia-related psychosis
Any drugs or conditions that prolong QT interval
Recent acute myocardial infarction
Uncompensated heart failure
Seizure disorders; may cause hypotension, EPS, somnolence, and sensory instability, which could lead to falls and, consequently, fractures or other injuries; for patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy
Atypical antipsychotics have been associated with metabolic changes (eg, hyperglycemia, dyslipidemia, and body weight gain) that may increase cardiovascular/cerebrovascular risk
Hyperglycemia may occur and in some cases may be extreme, resulting in ketoacidosis, hyperosmolar coma, or death; monitor blood glucose of high-risk patients
Neuroleptic malignant syndrome reported with antipsychotic drugs
Tardive dyskinesia, acute dystonic reactions, pseudoparkinsonism, or akathisia may develop acutely or chronically
Discontinue if rash develops without an identified cause
Drug reaction with eosinophilia and systemic symptoms (DRESS) reported; DRESS consists of combination of three or more of the following: cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, lymphadenopathy and one or more systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and pericarditis; DRESS is sometimes fatal; discontinue therapy if DRESS suspected
Cutaneous adverse reactions, such as Stevens-Johnson syndrome, reported; severe cutaneous adverse reactions are sometimes fatal; discontinue therapy if suspected
Rare cases of priapism reported
FDA warning regarding off-label use for dementia in elderly (see Black Box Warnings)
May cause orthostatic hypotension
Suicide attempt is inherent in psychotic illness or bipolar disorder, close supervision of high-risk patients should accompany drug therapy
Dopamine2 antagonists may elevate prolactin levels; long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density
Leukopenia/neutropenia and agranulocytosis reported; possible risk factors for leukopenia/neutropenia include preexisting low white blood cell (WBC) count and history of drug-induced leukopenia/neutropenia
If patient has history of clinically significant low WBC count or drug-induced leukopenia/neutropenia, monitor complete blood count (CBC) frequently during first few months of therapy; discontinue drug at first sign of clinically significant WBC decline
Antipsychotic agents have been associated with esophageal dysmotility and aspiration; use caution in patients at risk of pneumonia
May cause QTc prolongation, which has been associated with development of malignant ventricular arrhythmias (torsade de pointes) and sudden death; discontinue therapy in patients with persistent QTc intervals >500 msec; avoid hypokalemia or hypomagnesemia
Moderate to highly sedative; use caution when required to operate heavy machinery
May cause core body temperature regulation impairment; use caution with heat exposure, strenuous exercise, dehydration, or taking medications with anticholinergic effects
Make electrolyte imbalance corrections, especially hypomagnesemia or hypokalemia before and throughout therapy
Use with caution in hepatic impairment
Escitalopram plus adjunctive ziprasidone may lead to weight gain and akathisia and require additional monitoring of patients with major depressive disorder (MDD), but ziprasidone augmentation appears safe overall, according to research published in the Journal of Clinical Psychiatry.
David Mischoulon, MD, PhD, from the Depression Clinical and Research Program at Massachusetts General Hospital in Boston, and colleagues conducted a randomized, double-blind, placebo-controlled study of patients with persistent MDD (Ziprasidone Augmentation of SSRIs for Patients With Major Depressive Disorder That Do Not Sufficiently Respond to Treatment With SSRIs; ClinicalTrials.gov identifier: NCT00633399). Outpatients (n=139) were recruited after an 8-week open-label trial of escitalopram.
During the initial 8-week study period, participants from 3 academic medical centers in Boston, Massachusetts; Birmingham, Alabama; and Nashville, Tennessee, received escitalopram 10 to 30 mg/day. During the first 4 weeks, escitalopram doses increased by 10 mg/week, stabilizing at week 4. After enrollment in the 8-week open-label expansion, participants randomly received either adjunctive ziprasidone (escitalopram plus ziprasidone 20-80 mg twice daily; n=71) or escitalopram plus placebo (n=68). Mean doses of escitalopram were 21±5.8 mg/day and 19.2±3.1 mg/day in the ziprasidone and placebo groups, respectively.
Body mass index, weight, low-density lipoprotein-cholesterol and high-density lipoprotein-cholesterol, triglycerides, fasting glucose, HbA1c, thyroid-stimulating hormone, and prolactin levels were assessed at baseline and again at the conclusion of the double-blind phase. Measurements for all parameters were comparable at baseline between both groups (P >.05). No significant changes were recorded in most measures by week 8, although ziprasidone therapy resulted in a “significantly greater” weight increase than placebo (net difference, 2.5 kg; P =.03).
Although baseline QTc measures were also similar between groups, QTc increased by a mean 8.8 milliseconds by week 8 in the ziprasidone group (P =.06), so a significant association was noted between ziprasidone dose and QTc prolongation.
Patients in the ziprasidone group experienced a significantly higher baseline Barnes Akathisia Scale score for 1 item (objective); the other 3 items (subjective awareness of restlessness, distress related to restlessness, and global clinical assessment of akathisia) were similar between groups. During the study period, Barnes Akathisia Scale scores for item 4 increased in the ziprasidone group and decreased in the placebo group (P =.01).
“Adjunctive ziprasidone when combined with the escitalopram in MDD patients…demonstrated a mild increase in QTc that is deemed unlikely to be of broad clinical relevance,” the researchers wrote. “The positive efficacy findings for this combination supported its use as an effective augmentation of an SSRI, and our current results also support relative safety of the combination therapy.”
“However, in view of the developing concerns and warning about SSRIs and QTc prolongation, clinicians should carefully weigh the pros and cons of this combination,” they concluded.
The current study focused on efficacy, safety, and tolerability of adjunctive ziprasidone; it is unclear whether results would have been different if other antidepressants were used in conjunction with ziprasidone.
- Multiple inclusion and exclusion criteria were included in the current study, and it is unknown whether more cardiovascular or metabolic effects would have been seen in patients who did not meet inclusion criteria.
Drs Mischoulon, Shelton, Bobo, Fava, and Papakostas report receiving a variety of research support, consulting, and speaking honoraria and grant funding from Pfizer and Forest Pharmaceuticals.
Mischoulon D, Shelton R, Baer L, et al. Ziprasidone augmentation of escitalopram for major depressive disorder: cardiac, endocrine, metabolic, and motoric effects in a randomized, double-blind, placebo-controlled study. J Clin Psychiatry. doi: 10.4088/JCP.15m10426
Ziprasidone Augmentation May Have Benefits in Depression
The antipsychotic ziprasidone may be an efficacious adjunct to escitalopram for patients with non-psychotic unipolar major depressive disorder, according to a study published in the American Journal of Psychiatry.
George I. Papakostas, MD, and colleagues conducted a randomized, double-blind, parallel-group, placebo-controlled trial that included 139 participants at three academic medical centers. Participants were randomly assigned to one of two groups during the 8-week study—one group received escitalopram with adjunctive ziprasidone and the other group received escitalopram and adjunctive placebo.
Participants were followed-up weekly for 8 weeks, and the primary outcome was at least a 50% reduction in score on the Hamilton Depression Rating Scale (HAM-D). After 8 weeks, 35.2% of participants improved in the group with adjunctive ziprasidone compared with 20.5% in the placebo group.
Some secondary outcome measures also were greater in the adjunctive ziprasidone group. Participants improved more on the Hamilton Anxiety Rating Scale (HAM-A), though they did not improve on the Visual Analog for Pain score.
While none of the patients in the placebo group stopped treatment due to intolerance, 14% of patients in the adjunctive ziprasidone group discontinued treatment for that reason.
“These results suggest that, similar to other atypical antipsychotic agents, adjunctive ziprasidone can represent a useful treatment option for patients with major depressive disorder,” the study’s authors concluded.
Ziprasidone as Adjunctive Therapy in Severe Bipolar Patients Treated with Clozapine
Aim. To confirm the efficacy and tolerability of ziprasidone as adjunctive therapy in bipolar patients partially responding to clozapine or with persisting negative symptoms, overweight, or with metabolic syndrome. Methods. Eight patients with psychotic bipolar disorder were tested with the BPRS, the HAM-D, and the CGI at T0 and retested after 2 weeks (T1). Plasma clozapine and norclozapine levels and BMI were tested at T0 and T1. Results. Ziprasidone was well tolerated by all the patients. BPRS and HAM-D scores were reduced in all patients. BMI was reduced in patients with a BMI at T0 higher than 25. Plasma levels of clozapine and norclozapine showed an irregular course.
Atypical antipsychotics (also known as second generation antipsychotics, SGAs) have proven effective in the treatment of schizophrenia and schizoaffective disorder yielding improvements in both positive and negative symptoms .
Many SGAs are also indicated for the treatment of the different phases of bipolar disorder (BD) (i.e. acute mania and depression and maintenance) in monotherapy and in association with mood stabilizers. The SGAs vary widely in their efficacy/tolerability profiles allowing a better personalization of pharmacotherapy .
SGAs have represented a meaningful improvement in clinical management of BD but a substantial percentage of patients keep on experiencing relapses, continuous cycling, persistent affective and psychotic symptoms, and functional deterioration .
Clozapine, the “gold standard” of SGAs, has never been approved for the treatment of bipolar disorder, though it has showed efficacy in acute mania and in the treatment of severe psychotic bipolar disorder. This latter has been suggested to represent a possible intermediate clinical phenotype placed in the continuum of major psychoses bridging typical bipolar disorder to schizophrenia through schizoaffective disorder .
A significant percentage of patients with severe psychotic bipolar disorder exhibit poor or incomplete response to usual monotherapy and combination treatments of adequate dosages and duration. Clozapine has been proposed as a suitable rescue choice to manage such complex conditions including uncontrollable mood instability, agitation, insomnia, psychosis, and aggressiveness. Unfortunately, even the addition of clozapine to the therapeutic strategy often leads only to a partial response . Moreover, clozapine treatment is burdened with several short- and longer-term side effects such as sialorrhoea, oversedation, increased appetite leading to weight gain, new-onset diabetes, dyslipidemia and metabolic syndrome .
Many studies focusing mostly on schizophrenia samples have proposed distinct adjunctive antipsychotics in order to promote clinical remission, to attempt a clozapine dose reduction, and/or to mitigate its side effects .
Although the combination of two or more antipsychotics in bipolar disorder is poorly documented and, to our knowledge, not supported by randomized clinical trials, it is a common strategy in clinical practice : about 15% of psychotic bipolar outpatients and 50% of inpatients receive more than one antipsychotic .
We have previously reported that the augmentation of clozapine with aripiprazole may be safe and effective in severe psychotic schizoaffective and bipolar disorder which failed to respond to SGAs .
Ziprasidone is an atypical antipsychotic recently introduced in the Italian market, approved for the treatment of schizophrenia in adults and also for the treatment of bipolar manic or mixed episodes of moderate severity in adults, adolescents, and children (aged between 10 and 17), with a reported low potential for extrapyramidal side effects.
Given its antagonistic activity on serotonin 5-HT2A, 5-HT1D, and 5-HT2C receptors and the agonist partial activity on 5-HT1A receptors as well as the moderate in vitro-inhibitory activity on serotonin and noradrenaline transporters, ziprasidone has been suggested to display efficacy on depressive and negative symptoms . Ziprasidone, in conjunction with mood stabilizers, could promisingly offer additional mood regulating, antidepressant, and anxiolytic actions .
Its low affinity for H1 histaminergic, alpha1 adrenergic, and M1 muscarinic receptors predicts a safe tolerability profile with a low potential, respectively, for weight gain, hyperglycemia, cholesterol and triglyceride dysregulation, orthostatic hypotension and cardiovascular side effects, sedation, and cognitive impairment . Because of this favourable side effect profile and low risk of pharmacologic interactions, ziprasidone is a suitable candidate for clozapine augmentation.
The association of ziprasidone to an ongoing clozapine treatment has proven effective in severe psychotic patients bringing about improvements of negative/cognitive symptoms and of clozapine related side effects, with only a minor QTc interval prolongation .
Aims of this paper are to report on the potential efficacy and tolerability of the clozapine-ziprasidone association in a case series of severe psychotic bipolar patients resistant to previous medication trials and to provide preliminary data on possible pharmacokinetic interactions between the two antipsychotics.
2. Material and Methods
Patients were recruited in the Inpatient Psychiatric Unit of the Department of Psychiatry at Pisa University. All patients received a diagnosis of bipolar disorder with psychotic symptoms by the treating clinician according to the DSM-IV criteria .
Eligibility criteria were the following: (1) age of 18–65 years, (2) resistance/inadequate response to at least two trials of mood stabilizers (i.e. lithium salts, valproic acid, and carbamazepine) and/or of antipsychotics prescribed at adequate dosages, for at least six months, (3) treatment with clozapine at least six months ago, (4) relevant mood swings associated with persistent psychotic symptoms despite the treatment with clozapine, (5) no contraindications to ziprasidone treatment (e.g., prolonged QTc interval), (6) normal bone marrow and hepatic and renal functions, (7) capability to attend follow-up visits, and (8) proved compliance to treatment as indicated by blood levels monitoring.
On the contrary, exclusion criteria were as follows: (1) history of drug abuse/dependence within six months from enrolment, (2) diagnosis of neurologic disorders such as Parkinson’s disease, epilepsy, and myasthenia gravis, (3) jaundice or haematological diseases, (4) pregnancy or breast-feeding, and (5) current major depression.
Administration of other psychotropic medications other than clozapine and ziprasidone was allowed as clinically needed and recorded as well.
According to usual monitoring protocols implemented at our Inpatient Psychiatric Unit, patients underwent assessments with a number of clinical rating scales, systematic recording of side effects, laboratory tests, body mass index (BMI) monitoring, and measurement of clozapine and norclozapine plasma levels.
Clozapine and norclozapine plasma levels recorded within patients’ case report forms were considered for the aims of the present study on the day before (T0) and 15 days after (T1) ziprasidone introduction. The measurement of plasma drug levels was performed in fasting condition three hours after the clozapine morning dose, which corresponds approximately to the time of clozapine peak concentration. BMI and concomitant therapies information was collected at T0 and T1 as well as any unwanted effects of medications. All patients provided written consent to the review of their case histories.
2.1. Efficacy and Tolerability Assessments
The Mini International Neuropsychiatric Interview (M.I.N.I.) was administered at T0 to confirm diagnosis. Clinical features and disease severity were evaluated by means of the Brief Psychiatric Rating Scale 24 items (BPRS), the Hamilton Depressive Rating Scale (HAM-D), and the Clinical Global Improvement (CGI).
2.2. Laboratory Analysis
Blood samples (5 mL) for clozapine plasma levels measurement were withdrawn from a peripheral vein of the forearm, collected within heparinized tubes, and immediately centrifuged. Plasma was stored at −20°C until the actual measurement of drug levels.
Plasma concentrations of clozapine and its active metabolite were determined by the high performance liquid chromatography (HPLC) method, using a commercially available kit (Chromsystems, Munchen, Germany), following the instructions of manufacturers. The clozapine/norclozapine plasma concentration ratio was calculated as an index of drug metabolism in patients, while levels of the drug and the metabolite were normalized by the daily clozapine dose in order to reduce interpatient variability.
2.3. Statistical Analysis
BPRS, HAM-D, and CGI scores before and after ziprasidone association were compared using the Wilcoxon signed rank test. Statistical significance was set at 2-sided (StataCorp. 2007. Stata Statistical Software: Release 10. College Station, TX: StataCorp LP).
3.1. Clinical Characteristics
Eight patients (6 males and 2 females) were enrolled from May 2011 to September 2011. All subjects were diagnosed with bipolar disorder, mixed episode with psychotic features. One patient received the additional diagnosis of social phobia and one patient of comorbid panic disorder.
Before ziprasidone augmentation, patients had been assuming clozapine at a mean dosage of 140.6 mg daily (range 50–250 mg daily) for at least 6 months. All patients were at clozapine steady state and previous controls had demonstrated stable plasma concentrations. Moreover, all patients had been taking all the other drugs (see Table 3) for at least a period of 30 days before the study initiation.
Ziprasidone was added to the ongoing therapy starting at a dose of 40 mg twice daily up to a final total daily dose of 120–160 mg/day (mean dose: 155 mg/day).
3.2. Metabolic Parameters
Cholesterol and triglycerides plasma levels were tested at T0. No patients showed severe metabolic dysfunctions (see Table 1). One patient had a second grade obesity (BMI 36.6), two patients had a first grade obesity (BMI of 30 and 32, resp.), three were overweight (BMI of 27.7, 27, and 26, resp.), and two had a normal BMI (see Table 4).
Table 1 Metabolic parameters before and after the addition of ziprasidone.
3.3. Clozapine, Norclozapine Plasma Levels and Clozapine/Norclozapine Ratio
Mean plasma levels of clozapine and norclozapine at T0 were 0.172 mg/L and 0.143 mg/L, respectively. Mean plasma levels of clozapine and norclozapine at T1 were 0.304 mg/L and 0.119 mg/L, respectively.
After the adjunction of ziprasidone the clozapine dosage was reduced in 2 patients and increased in other 3 patients. As a whole, plasma levels of clozapine and norclozapine fluctuated for each patient irregularly and irrespective of drug dosage modifications.
3.4. Concomitant Treatments
After the augmentation with ziprasidone concomitant psychotropic treatments were reduced in all patients with the exception of one (see Table 2).
Table 2 Concomitant treatments at T0 and T1.
Table 3 Percentage of improvement at BPRS, HAM-D, and CGI. Table 4 Percentage of BMI improvement after ziprasidone augmentation.
3.5. Severity Assessment
At T1, the majority of the patients displayed a significant improvement of symptom severity as assessed by BPRS (, ), CGI (, ), and HAM-D (, ) rating scales. Specifically, the mean BPRS anxiety depression domain score decreased from 11.4 at T0 to 8.1 at T1; the anergy domain varied from 12.9 to 8.7; the thought disorder domain decreased from 13.4 to 9.5; the psychomotricity domain changed from 5.9 to 4.75; lastly, an improvement from 7.7 at T0 to 5.7 at T1 was detected in the suspiciousness hostility domain.
One patient showed an HAM-D score worsening at T1 due to a higher level of psychic and somatic anxiety. This patient was the one diagnosed with comorbid panic disorder (Table 3).
3.6. Side Effects
No treatment emergent side effects were apparently attributable to ziprasidone prescription.
4. Supplementary Data
The reduction of valproic acid was possible in one patient (number 8). Two patients needed to stop lithium therapy because of the onset of psoriasis and the worsening of glomerulonephritis, respectively. In patients 2, 3, 5, and 6 haloperidol was suspended. In patient 2 escitalopram was withdrawn as well. Finally, bromperidol was stopped in patient 7.
The efficacy and safety of the combination ziprasidone- clozapine in patients with schizophrenia have been proved in previous studies . The efficacy of ziprasidone as monotherapy or in combination with mood stabilizers in patients with bipolar I disorder has been previously reported . Conversely, other authors failed to show efficacy of ziprasidone for different bipolar phases .
To our knowledge, this is the first study to evaluate efficacy and tolerability of the clozapine-ziprasidone combination for persistent mood instability and psychotic symptoms in bipolar patients with burdensome overweight and other treatment emergent side effects.
The augmentation of clozapine with ziprasidone was associated with unequivocal improvements of both psychotic and affective symptoms. In fact, all of the patients showed a score reduction on different BPRS domains and amelioration of depressive symptoms as assessed by the HAM-D. Our findings confirm previous reports suggesting a possible antidepressant effect of ziprasidone in patients suffering from bipolar type I or type II depression . Furthermore, we noticed that the addition of ziprasidone alleviated the clinical burden of clozapine related side effects such as sialorrhea and weight gain.
In our sample, only one patient with comorbid panic disorder worsened after the addition of ziprasidone because of an increase of the HAM-D anxiety score. This may suggest caution or a different dosage titration of ziprasidone in subjects with anxiety symptoms, slightly in contrast with prior open-label and placebo-controlled evidences of ziprasidone efficacy in refractory generalized anxiety disorder (GAD) . However, in the double-blind controlled study on GAD, ziprasidone was prescribed to lower flexible doses (i.e., 20–80 mg versus 80–160 daily in our report).
Kaushik et al. described the case of a patient aged 43 with schizoaffective disorder who had showed psychomotor activation after the prescription of high dose ziprasidone treatment. After nine days of ziprasidone monotherapy (at a dose of 320 mg/day), the authors reported the appearance of psychomotor restlessness, irritability, anxiety, and akathisia . According to the data available in the literature and based on what we observed in our sample, as well as in relation to the pharmacodynamics of ziprasidone, it could be argued that lower doses are associated with more anxiolytic properties and fewer extrapyramidal side effects while higher doses may be associated with akathisia and the loss of anxiolytic effects.
As shown by the nonlinear variations of clozapine/norclozapine plasma levels before and after ziprasidone introduction, the efficacy of ziprasidone was not related to a pharmacokinetic interaction with clozapine. Accordingly, Ziegenbein et al. (2005) have demonstrated that clozapine and ziprasidone undergo different metabolic pathways, with the former metabolized by the cytochrome P450 system and the latter mostly through aldehyde oxidation .
The additional dopamine D2 antagonistic action of ziprasidone may enhance the relatively weak D2 blockade exerted by clozapine and partially explain the clinical improvement produced by this combination. Furthermore, ziprasidone displays serotonin and noradrenaline reuptake inhibition properties and 5HT1C agonist activity ; this is offering other reasonable explanations for its benefits on mood and psychomotor symptomatology.
Ziprasidone was well tolerated in all of the patients. No patient needed to stop the drug due to treatment emergent side effects. Adjunctive ziprasidone resulted in a BMI reduction in the vast majority of subjects, according to other published findings , except for those two patients who had a normal BMI at the initial assessment. Moreover, Ziprasidone was associated with the withdrawal of concomitant antipsychotics in all the patients but two (see Table 2). These findings are promisingly in keeping with results from schizophrenia trials and small studies suggesting that ziprasidone may allow a dose reduction/discontinuation of coprescribed medications, decrease appetite, and even bring about a sizeable weight loss .
6. Study Limitations
This is a small naturalistic short-term case series of the clozapine-ziprasidone combination for severe psychotic bipolar patients. The promising results we have shown both in improved efficacy and in tolerability need to be confirmed in larger size and longer-term studies focused also on relapse prevention and assessment of global functioning. Given that clozapine is not indicated for bipolar disorder and should be considered an exceptional rescue treatment, it is unlikely that controlled trials will be performed. Therefore, our choices will have to rely mostly on clinical experience and case reports. In future, a more precise evaluation of psychopathological dimensions (e.g. energy levels, mood, proneness to psychosis, sleep, etc.) affected by ziprasidone augmentation will help to refine our opinion on this therapeutic strategy. In the absence of other risk factors for QTc prolongation/cardiac arrhythmias, ziprasidone prescription does not demand electrocardiogram monitoring . Nevertheless, it would be interesting to add information about QTc variations in next studies, as Kuwilsky et al. (2010) have already recorded a statistically significant QTc elongation in schizophrenic patients treated with the clozapine-ziprasidone association .
Conflict of Interests
The authors declare that there is no conflict of interests regarding the publication of this paper.