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layer that dissolves quickly to help people fall asleep fast and an inner core that breaks down more slowly so that they wake up in the morning without lingering drowsiness.

But because of the digestive cycle, pills can only last about a day in the body. So, many companies are focusing their attention on injections. Long-acting injections mean that people with advanced prostate cancer, for example, can receive a shot of Abbott Laboratories’s hormone-regulating drug Lupron that lasts four months. In March, the US Food and Drug Administration (FDA) also approved a twice-yearly injection of a similar drug agent called Trelstar, developed by California-based Watson Pharmaceuticals for the same disease.

“The market is demanding controlled release technology,” says Cheryl Barton, director of the Chichester, UK–based biomedical consultancy Pharmavision. She

the strongest advocates for the use of long-acting injections to treat schizophrenia.

Sitting in his office at a conference table stacked with books and papers, Kane recalls a man in his mid-20s who had been inconsistent about taking his medicines for the previous three years. “After the second relapse,” Kane says, “then we started talking about, ‘What about using long-acting injectables?’” After initially resisting, the young man decided to give it a try. It worked—he managed to hold a steady job for the first time in his life.

Time-release drug delivery has come a long way since the early 1950s, when the chemical engineer Hans Lowey pioneered a slow-acting salt tablet to help American troops fighting in the Korean War retain water. Nowadays, most people have some familiarity with drugs that contain time-release technology. The sleeping pill Ambien CR (from Sanofi Aventis), for instance, contains an outer

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The shiny shovel propped up in a corner of John Kane’s office commemorates the groundbreaking of the new outpatient center at the Zucker Hillside Hospital eight years ago. For Kane, chairman of psychiatry at the New York hospital, the construction of the building marked yet another transformation of the campus where he has worked since 1971. Back when he started here doing his medical residency, the 223-bed facility had tennis courts and a flower garden for patients living there. The courts are gone now, and the garden is a parking lot—the loss of these spaces reflects the fact that patients at present typically stay less than 30 days at the hospital rather than many months at a time.

Kane no longer sees patients, but his three decades directly involved in clinical care taught him that people do not always comply with the daily pill regimen they are prescribed. As a result, he has become one of

Beginning in the 1970s, some hospitalized patients with schizophrenia began receiving drug injections that lasted for weeks in place of their daily antipsychotic pills. These extended doses helped them stick to their prescribed course of medicine but also carried the risk of causing irreversible neurological damage. Roxanne Khamsi reports on how newer versions of such long-acting injectables might radically change the treatment of ailments ranging from alcoholism to diabetes.

Timing is everything

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refused to take their prescribed medicines.Over the decades of his work in psychiatry,

Tim Lambert has witnessed people going to great lengths to skip doses. “Patients are experts at spitting things out, even two or three hours later. Some people call it ‘cheeking the tablets’,” says Lambert, head of schizophrenia treatment and outcomes research at the University of Sydney’s Brain and Mind Research Institute.

In the 1970s, Lambert and his colleagues experienced a push to treat people with schizophrenia on an outpatient basis, rather than keeping them hospitalized. The change was a result of what he calls an “unholy alliance” between human rights groups, which felt people with psychiatric disorders deserved greater autonomy, and governments, which saw an opportunity to cut costs. Long-acting injections of antipsychotic drugs meant that some patients could leave the hospital where they would otherwise have had to stay so that staff could observe them taking their pills every day.

Lambert estimates that in the 1970s about 60% of people being treated for schizophrenia in Australia received long-acting deposits of drugs dubbed ‘depots’. Studies have estimated that as much as 80% of outpatients with psychosis in the UK received such injections; the use of these injections hovered lower, at less than 20%, in the US (Br. J. Psychiatry 195, s7–s12, 2009).

For all of their promise, the oil-based shots had some major downsides. Pain and itching often occurred at the site of injection. Even worse, many patients developed an irreversible form of involuntary, repetitive body movements known as tardive dyskinesia. Although these types of first-generation long-acting antipsychotics enjoyed some popularity decades ago, their use declined dramatically in the 1990s with the introduction of a new class of schizophrenia drugs known as ‘atypical antipsychotics’. These innovative drugs came in pill form and improved patient outcome with fewer neurological side effects.

In 2003, the FDA approved the first long-acting injectable formulation of an atypical antipsychotic. The medicine, called Risperdal Consta, is a version of the Johnson & Johnson drug risperidone—an atypical antipsychotic—loaded into microspheres about the width of a human hair. To create this combination, Alkermes, a biotech headquartered in Waltham, Massachusetts, takes the drug and dissolves it in a solution containing the polymer polylactide co-glycolide (PLG), the same biodegradable polymer used in surgical sutures. That mixture is then combined with water, causing small microsphere droplets of

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the PLG-drug combination to form. When the microspheres are ultimately injected, they sit just under the skin, and, as the PLG dissolves over the course of a couple of weeks, it gradually releases the drug.

Alkermes is by no means alone in developing time-release antipsychotics. Two years ago, European regulators approved Eli Lilly’s long-acting version of the schizophrenia drug olanzapine. This past December, the FDA approved the product, which is marketed as Zyprexa Relprevv and allows for sustained delivery for up to a month.

Kane, who advises companies such as Eli Lilly and Johnson & Johnson, would like to see long-acting antipsychotics become more widely offered to people. “I think it is an important option, and I think in the US it has been underutilized,” he says. He points to his patient who was able to hold a steady job after starting injectables as an instance where switching to long-acting drugs made a real difference.

Relapses, Kane emphasizes, represent the biggest challenge for most people living with schizophrenia. The disease often strikes in the late teens or early 20s, when people are in college or landing their first job. Severe episodes of delusions or extreme agitation may mean they have to take time off of school or work, sometimes multiple times. And although some institutions and employers are understanding of the situation, many are not. “Life’s opportunities erode quite rapidly after several episodes,” says Kane.

Many doctors expect the arrival of long-acting medicines to improve patient compliance and thereby reduce the rate of psychotic relapses. “In a sense, it could be a game changer,” says Lambert.

Joint effortsFrom a market research point of view, Pharmavision’s Barton sees increasing dialogue between companies that develop drugs and those that develop time-release technology. The chemical engineers behind these technologies are taking greater initiative in thinking up new applications. “They’re actually talking to the drug development guys much earlier,” she says. Proponents of this type of sustained release technology advocate that it extends both the drug’s effect and the patient’s life.

The types of drugs being turned into long-release formulations are expanding. Alkermes, for example, is developing long-acting drugs for rheumatoid arthritis and pain. The company also makes an FDA-approved once-monthly injectable for alcohol dependence called Vivitrol, and it is hoping

notes that patients like the convenience of once-a-day pills as opposed to having to remember to take multiple doses morning, noon and night. According to a 2009 Pharmavision report, medications using controlled release technology generate annual sales in excess of $20 billion. And although the majority of such sales currently derive from pill formulations, injectables are on the rise, Barton says.

Doctors have to take steps to prevent adverse drug reactions before dosing people at extended intervals. Still, long-acting injectable drugs are now being used to treat disparate diseases such as osteoporosis and bipolar disorder, and for contraception. Scientists have also started developing injections for extended delivery of HIV and hepatitis drugs. For the global health community, these types of injections could be a boon for treating sick people in remote areas where regular delivery of drugs can present a challenge.

Starting with sesameAn early milestone in the history of long-acting injectables came in 1966, when the antipsychotic medicine fluphenazine enanthate was mixed with sesame oil so that it would release over the course of two weeks after being injected into the buttocks. This and similar injections were designed in part to address the problem of patients who

Digging for solutions: John Kane in his office at the Zucker Hillside Hospital.

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for approval this year of its long-acting diabetes drug, Bydureon (which it developed in partnership with Amylin Pharmaceuticals and Eli Lilly).

Bydureon is based on a compound that mimics the action of glucagon-like peptide-1 (GLP-1), a molecule that helps control blood glucose concentrations. A resilient functional analog of the human protein was identified in the saliva of the Gila monster lizard in the 1990s, which sent many companies exploring into how to make a long-lasting GLP-1–based drug.

Alkermes’ Bydureon is designed to be given once a week, and many other companies are now in the game to produce similarly lasting GLP-1–related drugs. One company, Montreal-based ConjuChem, has high hopes for its so-called macromolecular conjugate form of a compound that activates the GLP-1 receptor. The ConjuChem compound circulates in the body once injected, unlike depot forms of injectables, which sit under the skin or in muscle.

Rather than embedding its drug in a polymer matrix, as some companies do, ConjuChem attaches its peptide to a recombinant form of albumin, the most common protein found in human blood. “When you link it up to a big protein like albumin, it doesn’t get peed out quickly,” explains Thomas Ulich, who heads the company’s research and development

arm. As such, the GLP-1-receptor agonist circulates though the body, dissociating from the albumin over time.

ConjuChem announced results from a 224-person phase 2 trial involving its conjugated GLP-1 receptor agonist, PC-DAC:Exendin-4. The results, which have not yet been submitted for publication, showed a statistically significant improvement in blood sugar levels. The pharma giants Pfizer and GlaxoSmithKline have also investigated long-acting products that act on the GLP-1 pathway.

Novo Nordisk has meanwhile tried to extend the activity of its once-a-day GLP-1 analog liraglutide. Adding a fatty-acid side chain to the liraglutide molecule causes the drug to link up seven at a time, the company found. “It’s like seven Legos together,” says Alan Moses, chief medical officer of Novo Nordisk. “The difference is that these ‘Legos’ come apart, which the plastic pieces aren’t very good at doing,” thereby allowing the drug molecules to dissociate over time in the circulatory system.

Extended considerationLong-acting injectable drugs usually carry the same side effect risks as their pill-form counterparts, but they have some unique risks as well. There is some evidence, for example, that in very rare instances people receiving

the long-acting drug Zyprexa Relprevv can experience what’s known as post-injection delirium—when the drug acts too quickly in the system after initial delivery and causes sleepiness. The danger, cautions Lambert, is that somebody might experience this effect at an inopportune time. “It’s very unsafe if you’re driving a car,” he says.

So far, no patient has died as a result of post-injection delirium, notes Wolfgang Fleischhacker, a psychiatrist at the Medical University Innsbruck in Austria. “But, theoretically, every intoxication is potentially fatal,” he says, “which is why the regulators in the US and the EU have issued warnings in the label, and the drug can only be used with strict safety precautions, such as a mandatory three-hour observation period after the injection.” Fleischhacker doesn’t blame the drugs themselves, but says there might be ways to improve injection procedures to avoid this risk.

The issue of side effects is one reason why many developers hesitate to invest in long-acting injectables that are given at intervals several months apart. The risk is that if a person reacts unfavorably to the drug it becomes problematic to figure out how to reverse the situation. As a workaround, doctors usually prescribe a person the daily form of a drug before switching him or her to the long-acting version.

In many parts of the world, price has proven to be another major deterrent to long-acting drugs. “There’s a price to be paid for the convenience of those products,” says Barton. This, she notes, has resulted in uneven adoption of time-release medications from country to country. “One of the biggest markets for this has been the US,” she explains, but European countries with nationalized health systems seem less keen to pay for such medications.

Some studies have suggested a cost savings from long-acting antipsychotics when it comes to hospitalizations. One small study that followed 100 people with schizophrenia for a year after they were put on long-acting risperidone counted a total of 22 hospital admissions during that period, compared with 62 admissions in the previous year (J. Psychopharmacol. 22, 128–131, 2008).

Lambert laments that such findings do not get discussed more often. “I’d have to say that this literature is suppressed,” he says. For all their promise, it remains unclear whether long-acting injectables will gain more traction. Only time will tell.

Roxanne Khamsi is the senior news editor at Nature Medicine in New York.

Beyond blue-sky thinking: The Alkermes headquarters in Waltham, Massachusetts.

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