Drug Name

Abilify (Aripiprazole)

Generic Name

Aripiprazole (AR-i-PIP-ra-zole)

Looks like

Abilify Tablets are available in 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, and 30 mg strengths.

• Abilify 2 mg-green, modified rectangle tablets
• Abilify 5 mg-blue, modified rectangle tablets
• Abilify 10 mg-pink, modified rectangle tablets
• Abilify 15 mg-yellow, round tablets
• Abilify 20 mg-white, round tablets
• Abilify 30 mg-pink, round tablets

Dosage Form

Tablets

Route Of Administration

ORAL

Imprint Code

A-006;2 / A-007;5 / A-008;10 / A-009;15 / A-010;20 / A-011;30

Size

8mm / 8mm / 8mm / 6mm / 8mm / 9mm

Alternatives

Depression
Xanax, Lexapro (Escitalopram), Zoloft (Sertraline), Prozac (Fluoxetine), Cymbalta (Duloxetine), Desyrel (Trazodone)
Bipolar Disorder
Seroquel (Quetiapine), Zoloft (Sertraline), Lamictal (Lamotrigine), Clonidine, Klonopin
Schizophrenia
Seroquel (Quetiapine), Risperdal (Risperidone), Geodon (Ziprasidone), Zyprexa (Olanzapine)
Obsessive Compulsive Disorder
Zoloft (Sertraline), Prozac (Fluoxetine), Celexa (Citalopram), Paxil (Paroxetine)

Drug Uses

Abilify is used to treat the symptoms of psychotic conditions such as schizophrenia and bipolar disorder (manic depression). It is also used together with other medications to treat major depressive disorder in adults.

Drug class

Abilify is an antipsychotic medication. It works by changing the actions of chemicals in the brain.

Contains

Abilify Tablets are available in 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, and 30 mg strengths. Inactive ingredients include cornstarch, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. Colorants include ferric oxide (yellow or red) and FD&C Blue No. 2 Aluminum Lake.

Chemical formula

Aripiprazole is a psychotropic drug that is available as Abilify (aripiprazole) tablets, Abilify DISCMELT (aripiprazole) orally disintegrating tablets, Abilify (aripiprazole) oral solution, and Abilify (aripiprazole) injection, a solution for intramuscular injection. Aripiprazole is 7 - [4 - [4 - (2, 3 - dichlorophenyl) - 1 - piperazinyl]butoxy] - 3,4 - dihydrocarbostyril. The empirical formula is C23H27Cl2N3O2 and its molecular weight is 448.38. The chemical structure is:

Mechanism of Action

The mechanism of action of aripiprazole, as with other drugs having efficacy in Schizophrenia, Bipolar Disorder, Major Depressive Disorder, and agitation associated with Schizophrenia or Bipolar Disorder, is unknown. However, it has been proposed that the efficacy of aripiprazole is mediated through a combination of partial agonist activity at D2 and 5-HT1A receptors and antagonist activity at 5-HT2A receptors. Actions at receptors other than D2, 5-HT1A, and 5-HT2A may explain some of the other clinical effects of aripiprazole (eg, the orthostatic hypotension observed with aripiprazole may be explained by its antagonist activity at adrenergic alpha1 receptors).

How Taken

Take this medication exactly as it was prescribed for you. Do not take the medication in larger amounts, or take it for longer than recommended by your doctor.

Do not take Abilify for longer than 6 weeks unless your doctor has told you to. Take each dose with a full glass of water.

Abilify can be taken with or without food.

Abilify is usually taken once a day. Follow your doctor 's instructions.

Measure the liquid form of Abilify with a special dose-measuring spoon or cup, not a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist where you can get one.

To take Abilify orally disintegrating tablets (Abilify Discmelt):

• Keep the tablet in its blister pack until you are ready to take the medicine. Open the package and peel back the foil from the tablet blister. Do not push a tablet through the foil or you may damage the tablet.
• Using dry hands, remove the tablet and place it in your mouth. It will begin to dissolve right away.
• Do not swallow the tablet whole. Allow it to dissolve in your mouth without chewing.
• Swallow several times as the tablet dissolves. If desired, you may drink liquid to help swallow the dissolved tablet.

It is important to take Abilify regularly to get the most benefit.

To be sure this medication is helping your condition, your doctor will need to check your progress on a regular basis. It is important that you not miss any scheduled visits to your doctor.

Store Abilify tablets at room temperature away from moisture and heat.

Abilify oral solution should be stored in the refrigerator and can be used for up to 6 months after opening.

Dosage and Administration

Schizophrenia

Usual Dose

Adults

The recommended starting and target dose for Abilify is 10 mg/day or 15 mg/day administered on a once-a-day schedule without regard to meals. Abilify has been systematically evaluated and shown to be effective in a dose range of 10 mg/day to 30 mg/day, when administered as the tablet formulation; however, doses higher than 10 mg/day or 15 mg/day were not more effective than 10 mg/day or 15 mg/day. Dosage increases should not be made before 2 weeks, the time needed to achieve steady-state.

Adolescents

The recommended target dose of Abilify is 10 mg/day. Aripiprazole was studied in pediatric patients 13 to 17 years of age with Schizophrenia at daily doses of 10 mg and 30 mg. The starting daily dose of the tablet formulation in these patients was 2 mg, which was titrated to 5 mg after 2 days and to the target dose of 10 mg after 2 additional days. Subsequent dose increases should be administered in 5 mg increments. The 30 mg/day dose was not shown to be more efficacious than the 10 mg/day dose. Abilify can be administered without regard to meals.

Maintenance Therapy

Adults

While there is no body of evidence available to answer the question of how long a patient treated with aripiprazole should remain on it, systematic evaluation of patients with Schizophrenia who had been symptomatically stable on other antipsychotic medications for periods of 3 months or longer, were discontinued from those medications, and were then administered Abilify 15 mg/day and observed for relapse during a period of up to 26 weeks, has demonstrated a benefit of such maintenance treatment. Patients should be periodically reassessed to determine the need for maintenance treatment.

Pediatric Patients

The efficacy of Abilify for the maintenance treatment of Schizophrenia in the pediatric population has not been evaluated.

Switching from Other Antipsychotics

There are no systematically collected data to specifically address switching patients with Schizophrenia from other antipsychotics to Abilify or concerning concomitant administration with other antipsychotics. While immediate discontinuation of the previous antipsychotic treatment may be acceptable for some patients with Schizophrenia, more gradual discontinuation may be most appropriate for others. In all cases, the period of overlapping antipsychotic administration should be minimized.

Bipolar Disorder

Usual Dose

Adults

In clinical trials, the starting dose was 30 mg given once a day, without regard to meals. A dose of 30 mg/day was found to be effective when administered as the tablet formulation. Approximately 15% of patients had their dose decreased to 15 mg based on assessment of tolerability. The safety of doses above 30 mg/day has not been evaluated in clinical trials.

Pediatric Patients

Abilify has not been evaluated in pediatric patients with Bipolar Disorder.

Maintenance Therapy

While there is no body of evidence available to answer the question of how long a patient treated with aripiprazole should remain on it, adult patients with Bipolar I Disorder who had been symptomatically stable on Abilify Tablets (15 mg/day or 30 mg/day with a starting dose of 30 mg/day) for at least 6 consecutive weeks and then randomized to Abilify Tablets (15 mg/day or 30 mg/day) or placebo and monitored for relapse, demonstrated a benefit of such maintenance treatment. While it is generally agreed that pharmacological treatment beyond an acute response in Mania is desirable, both for maintenance of the initial response and for prevention of new manic episodes, there are no systematically obtained data to support the use of aripiprazole in such longer-term treatment (beyond 6 weeks). Physicians who elect to use Abilify for extended periods, that is, longer than 6 weeks, should periodically re-evaluate the long-term usefulness of the drug for the individual.

Adjunctive Treatment of Major Depressive Disorder

Usual Dose

Adults

The recommended starting dose for Abilify as adjunctive treatment for patients already taking an antidepressant is 2 mg/day to 5 mg/day. The efficacy of Abilify as an adjunctive therapy for Major Depressive Disorder was established within a dose range of 2 mg/day to 15 mg/day. Dose adjustments of up to 5 mg/day should occur gradually, at intervals of no less than 1 week. The long-term efficacy of Abilify for the adjunctive treatment of Major Depressive Disorder has not been established.

Pediatric Patients

The efficacy of Abilify for the adjunctive treatment of Major Depressive Disorder in the pediatric population has not been evaluated.

Agitation Associated with Schizophrenia or Bipolar Mania (Intramuscular Injection)

Usual Dose

Adults

The recommended dose in these patients is 9.75 mg. The effectiveness of aripiprazole injection in controlling agitation in Schizophrenia and Bipolar Mania was demonstrated over a dose range of 5.25 mg to 15 mg. No additional benefit was demonstrated for 15 mg compared to 9.75 mg. A lower dose of 5.25 mg may be considered when clinical factors warrant. If agitation warranting a second dose persists following the initial dose, cumulative doses up to a total of 30 mg/day may be given. However, the efficacy of repeated doses of aripiprazole injection in agitated patients has not been systematically evaluated in controlled clinical trials. The safety of total daily doses greater than 30 mg or injections given more frequently than every 2 hours have not been adequately evaluated in clinical trials.

If ongoing aripiprazole therapy is clinically indicated, oral aripiprazole in a range of 10 mg/day to 30 mg/day should replace aripiprazole injection as soon as possible.

Dosage Adjustment

Dosage adjustments are not routinely indicated on the basis of age, gender, race, or renal or hepatic impairment status.

Dosage adjustment for patients taking aripiprazole concomitantly with strong CYP3A4 inhibitors: When concomitant administration of aripiprazole with strong CYP3A4 inhibitors such as ketoconazole or clarithromycin is indicated, the aripiprazole dose should be reduced to one-half the usual dose. When the CYP3A4 inhibitor is withdrawn from the combination therapy, the aripiprazole dose should then be increased.

Dosage adjustment for patients taking aripiprazole concomitantly with potential CYP2D6 inhibitors: When concomitant administration of potential CYP2D6 inhibitors such as quinidine, fluoxetine, or paroxetine with aripiprazole occurs, aripiprazole dose should be reduced at least to one-half of its normal dose. When the CYP2D6 inhibitor is withdrawn from the combination therapy, the aripiprazole dose should then be increased.

Dosage adjustment for patients taking potential CYP3A4 inducers: When a potential CYP3A4 inducer such as carbamazepine is added to aripiprazole therapy, the aripiprazole dose should be doubled. Additional dose increases should be based on clinical evaluation. When the CYP3A4 inducer is withdrawn from the combination therapy, the aripiprazole dose should be reduced to 10 mg to 15 mg.

Missed Dose

Take the missed dose as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the medicine at the next regularly scheduled time. Do not take extra medicine to make up the missed dose.

Overdose

Seek emergency medical attention if you think you have used too much of this medicine. Overdose symptoms may include drowsiness, vomiting, agitation, aggression, confusion, tremors, fast or slow heart rate, seizure (convulsions), trouble breathing, feeling light-headed, or fainting.

Storage

Store Abilify at 77 degrees F (25 degrees C). Brief storage at temperatures between 59 and 86 degrees F (15 and 30 degrees C) is permitted. Store away from heat, moisture, and light. Do not store in the bathroom. Keep Abilify out of the reach of children and away from pets.

What is the most important information I should know about Abilify (Aripiprazole)?

Abilify is not for use in psychotic conditions that are related to dementia. Abilify has caused fatal heart attack and stroke in older adults with dementia-related conditions. Stop using Abilify and call your doctor at once if you have the following symptoms: fever with stiff muscles and rapid heart rate; uncontrolled muscle movements; symptoms that come on suddenly such as numbness or weakness, severe headache, and problems with vision, speech, or balance. Abilify can cause side effects that may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be awake and alert. Avoid drinking alcohol, which can increase some of the side effects of Abilify.

Avoid using other medicines that make you sleepy (such as cold medicine, pain medication, muscle relaxers, and medicine for seizures, depression or anxiety). They can add to sleepiness caused by Abilify. Tell your doctor if you regularly use any of these medicines.

Avoid becoming overheated or dehydrated. Drink plenty of fluids, especially in hot weather and during exercise. It is easier to become dangerously overheated and dehydrated while you are taking Abilify.

What should I discuss with my doctor before taking Abilify (Aripiprazole)?

Abilify is not for use in psychotic conditions that are related to dementia. Abilify has caused fatal heart attack and stroke in older adults with dementia-related conditions.

Before taking Abilify, tell your doctor if you have:

• liver or kidney disease;
• heart disease, high blood pressure, heart rhythm problems;
• a history of heart attack or stroke;
• a history of breast cancer;
• seizures or epilepsy;
• a personal or family history of diabetes; or
• trouble swallowing.

If you have any of these conditions, you may need a dose adjustment or special tests to safely take this medication.

The liquid form (oral solution) of this medication may contain up to 15 grams of sugar per dose. Before taking Abilify oral solution, tell your doctor if you have diabetes. The orally disintegrating tablet form of this medication may contain over 3 milligrams of phenylalanine per tablet. Before taking Abilify Discmelt, tell your doctor if you have phenylketonuria.

Abilify may cause you to have high blood sugar (hyperglycemia). Talk to your doctor if you have any signs of hyperglycemia such as increased thirst or urination, excessive hunger, or weakness. If you are diabetic, check your blood sugar levels on a regular basis while you are taking Abilify.

FDA pregnancy category C. This medication may be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment. Abilify can pass into breast milk and may harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

Absorption

Aripiprazole is well absorbed after administration of the tablet, with peak plasma concentrations occurring within 3 hours to 5 hours; the absolute oral bioavailability of the tablet formulation is 87%. Abilify can be administered with or without food. Administration of a 15 mg Abilify Tablet with a standard high-fat meal did not significantly affect the Cmax or AUC of aripiprazole or its active metabolite, dehydro-aripiprazole, but delayed Tmax by 3 hours for aripiprazole and 12 hours for dehydro-aripiprazole.

Distribution

The steady-state volume of distribution of aripiprazole following intravenous administration is high (404 L or 4.9 L/kg), indicating extensive extravascular distribution. At therapeutic concentrations, aripiprazole and its major metabolite are greater than 99% bound to serum proteins, primarily to albumin. In healthy human volunteers administered 0.5 mg/day to 30 mg/day aripiprazole for 14 days, there was dose-dependent D2 receptor occupancy indicating brain penetration of aripiprazole in humans.

Metabolism and Elimination

Aripiprazole is metabolized primarily by three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation. Based on in vitro studies, CYP3A4 and CYP2D6 enzymes are responsible for dehydrogenation and hydroxylation of aripiprazole, and N-dealkylation is catalyzed by CYP3A4. Aripiprazole is the predominant drug moiety in the systemic circulation. At steady-state, dehydro-aripiprazole, the active metabolite, represents about 40% of aripiprazole AUC in plasma.

Approximately 8% of Caucasians lack the capacity to metabolize CYP2D6 substrates and are classified as poor metabolizers (PM), whereas the rest are extensive metabolizers (EM). PMs have about an 80% increase in aripiprazole exposure and about a 30% decrease in exposure to the active metabolite compared to EMs, resulting in about a 60% higher exposure to the total active moieties from a given dose of aripiprazole compared to EMs. Coadministration of Abilify with known inhibitors of CYP2D6, such as quinidine or fluoxetine in EMs, approximately doubles aripiprazole plasma exposure, and dose adjustment is needed. The mean elimination half-lives are about 75 hours and 146 hours for aripiprazole in EMs and PMs, respectively. Aripiprazole does not inhibit or induce the CYP2D6 pathway.

Following a single oral dose of [14C]-labeled aripiprazole, approximately 25% and 55% of the administered radioactivity was recovered in the urine and feces, respectively. Less than 1% of unchanged aripiprazole was excreted in the urine and approximately 18% of the oral dose was recovered unchanged in the feces.

Special Populations

Geriatric

In formal single-dose pharmacokinetic studies (with aripiprazole given in a single dose of 15 mg), aripiprazole clearance was 20% lower in elderly (≥65 years) subjects compared to younger adult subjects (18 to 64 years). There was no detectable age effect, however, in the population pharmacokinetic analysis in Schizophrenia patients. Also, the pharmacokinetics of aripiprazole after multiple doses in elderly patients appeared similar to that observed in young, healthy subjects. No dosage adjustment is recommended for elderly patients.

Of the 12,925 patients treated with oral aripiprazole in clinical trials, 1061 (8%) were ≥65 years old and 799 (6%) were ≥75 years old. The majority (97%) of the 799 patients were diagnosed with Dementia of the Alzheimer's type.

Placebo-controlled studies of oral aripiprazole in Schizophrenia, Bipolar Mania, or Major Depressive Disorder did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Of the 749 patients treated with aripiprazole injection in clinical trials, 99 (13%) were ≥65 years old and 78 (10%) were ≥75 years old. Placebo-controlled studies of aripiprazole injection in patients with agitation associated with Schizophrenia or Bipolar Mania did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Studies of elderly patients with psychosis associated with Alzheimer's disease have suggested that there may be a different tolerability profile in this population compared to younger patients with Schizophrenia. The safety and efficacy of Abilify in the treatment of patients with psychosis associated with Alzheimer's disease has not been established. If the prescriber elects to treat such patients with Abilify, vigilance should be exercised.

Pediatric

Safety and effectiveness in pediatric patients with Bipolar Mania, Major Depressive Disorder, or agitation associated with Schizophrenia or Bipolar Mania have not been established.

Safety and effectiveness in pediatric patients with Schizophrenia were established in a 6-week, placebo-controlled clinical trial in 202 pediatric patients aged 13 to 17 years.

The pharmacokinetics of aripiprazole and dehydro-aripiprazole in pediatric patients 13 to 17 years of age were similar to those in adults after correcting for the differences in body weights.

Race

Although no specific pharmacokinetic study was conducted to investigate the effects of race on the disposition of aripiprazole, population pharmacokinetic evaluation revealed no evidence of clinically significant race-related differences in the pharmacokinetics of aripiprazole. No dosage adjustment is recommended based on race.

Renal Impairment

In patients with severe renal impairment (creatinine clearance <30 mL/min), Cmax of aripiprazole (given in a single dose of 15 mg) and dehydro-aripiprazole increased by 36% and 53%, respectively, but AUC was 15% lower for aripiprazole and 7% higher for dehydro-aripiprazole. Renal excretion of both unchanged aripiprazole and dehydro-aripiprazole is less than 1% of the dose. No dosage adjustment is required in subjects with renal impairment

Hepatic Impairment

In a single-dose study (15 mg of aripiprazole) in subjects with varying degrees of liver cirrhosis (Child-Pugh Classes A, B, and C), the AUC of aripiprazole, compared to healthy subjects, increased 31% in mild HI, increased 8% in moderate HI, and decreased 20% in severe HI. None of these differences would require dose adjustment.

Possible side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop using Abilify and call your doctor at once if you have any of these serious side effects:

• fever, stiff muscles, confusion, sweating, fast or uneven heartbeats;
• jerky muscle movements you cannot control;
• sudden numbness or weakness, headache, confusion, or problems with vision, speech, or balance;
• increased thirst or urination, loss of appetite, fruity breath odor, drowsiness, dry skin, nausea, and vomiting
• seizure (convulsions);
• thoughts of hurting yourself;
• feeling like you might pass out;
• jaundice (yellowing of your skin or eyes); or
• urinating less than usual or not at all.

Less serious side effects may include:

• choking or trouble swallowing;
• dizziness, drowsiness, or weakness;
• constipation, mild stomach upset;
• headache, anxiety;
• sleep problems (insomnia); or
• weight gain.

This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect.

What other drugs will affect Abilify (Aripiprazole)?

Before taking Abilify, tell your doctor if you are taking any of the following medicines:

• a medication to treat high blood pressure or a heart condition;
• carbamazepine (Tegretol), phenobarbital (Luminal, Solfoton), or phenytoin (Dilantin);
• rifabutin (Mycobutin) or rifampin (Rifadin, Rimactane, Rifater);
• ketoconazole (Nizoral), itraconazole (Sporanox);
• quinidine (Cardioquin, Quinaglute); or
• fluoxetine (Prozac), fluvoxamine (Luvox), or paroxetine (Paxil).

This list is not complete and there may be other drugs that can interact with Abilify. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor.

What should I avoid while taking Abilify (Aripiprazole)?

Abilify can cause side effects that may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be awake and alert.

Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall.

Avoid drinking alcohol, which can increase some of the side effects of Abilify.

Avoid using other medicines that make you sleepy (such as cold medicine, pain medication, muscle relaxers, and medicine for seizures, depression or anxiety). They can add to sleepiness caused by Abilify. Tell your doctor if you regularly use any of these medicines.

Avoid becoming overheated or dehydrated. Drink plenty of fluids, especially in hot weather and during exercise. It is easier to become dangerously overheated and dehydrated while you are taking Abilify.

Contraindications

Known hypersensitivity reaction to Abilify. Reactions have ranged from pruritus/urticaria to anaphylaxis.

Warnings and Precautions

Use in Elderly Patients with Dementia-Related Psychosis

Increased Mortality

Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. Abilify (aripiprazole) is not approved for the treatment of patients with dementia-related psychosis.

Cerebrovascular Adverse Events, Including Stroke

In placebo-controlled clinical studies (two flexible dose and one fixed dose study) of dementia-related psychosis, there was an increased incidence of cerebrovascular adverse events (eg, stroke, transient ischemic attack), including fatalities, in aripiprazole-treated patients (mean age: 84 years; range: 78-88 years). In the fixed-dose study, there was a statistically significant dose response relationship for cerebrovascular adverse events in patients treated with aripiprazole. Aripiprazole is not approved for the treatment of patients with dementia-related psychosis.

Safety Experience in Elderly Patients with Psychosis Associated with Alzheimer's Disease

In three 10-week, placebo-controlled studies of aripiprazole in elderly patients with psychosis associated with Alzheimer's disease (n=938; mean age: 82.4 years; range: 56-99 years), the treatment-emergent adverse events that were reported at an incidence of ≥3% and aripiprazole incidence at least twice that for placebo were lethargy [placebo 2%, aripiprazole 5%], somnolence (including sedation) [placebo 3%, aripiprazole 8%], and incontinence (primarily, urinary incontinence) [placebo 1%, aripiprazole 5%], excessive salivation (placebo 0%, aripiprazole 4%), and lightheadedness (placebo 1%, aripiprazole 4%).

The safety and efficacy of Abilify in the treatment of patients with psychosis associated with dementia have not been established. If the prescriber elects to treat such patients with Abilify, vigilance should be exercised, particularly for the emergence of difficulty swallowing or excessive somnolence, which could predispose to accidental injury or aspiration.

Clinical Worsening and Suicide Risk

Patients with Major Depressive Disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with Major Depress