Latuda: “Procognitive” or Pro-Profit? [Free Article]

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Schizophrenia

Lurasidone (Latuda) was approved by the FDA for schizophrenia in October 2010 and is the 10th atypical antipsychotic in our toolbox, believe it or not! Just to refresh your memory, the order of introduction of atypicals was: clozapine (Clozaril), risperidone (Risperdal), olanzapine (Zyprexa), quietiapine (Seroquel), ziprasidone (Geodon), aripiprazole (Abilify), paliperidone (Invega), iloperidone (Fanapt), asenapine (Saphris), and now lurasidone.

Both clozapine and risperidone are available in generic formulations, and Zyprexa’s patent will expire in October of 2011 (although Lilly is likely to be able to delay this with various lawsuits). Therefore, aside from clozapine and risperidone, atypical antipsychotics are still very expensive; lurasidone will be no exception, and the average dose will likely cost in the range of $5,000/year (vs generic risperidone’s $1,800/year).

The key question is: does lurasidone have any advantages over existing agents, or is it just another “me-too” drug?

Mechanism of Action
Like all other atypicals, lurasidone presumably works its antipsychotic magic by being a mixed D2/serotonin 5-HT2A antagonist. To refresh your memory on what this means, these meds theoretically quell core psychotic symptoms by blocking D2 receptors in the mesolimbic brain regions. But unlike typical antipsychotics, they also block serotonin 2A receptors in the nigrostriatal areas of the brain that govern involuntary movements. Since blocking serotonin tends to enhance dopamine activity, atypicals cause fewer movement disorders than typicals. They also are about one-tenth as likely to cause tardive dyskinesia.

When you add a large helping of Pharma promotion to these real advantages, you can understand why atypicals have become blockbuster medications, accounting for about $13 billion in yearly spending worldwide, according to a 2009 report (Rosenheck RA and Sernyak MJ, Health Affairs 2009;28(5):w782–w793). Coming back to lurasidone, does it offer any new mechanism aside from the tried and true D2/5-HT2A antagonism? The short answer is: we don’t know.

Lurasidone does a whole lot of things to various receptors. For example, it is a strong 5-HT7 antagonist. 5-HT what? Yes, our brains have 5-HT7 receptors, and they are vaguely said to “modulate” striatal and cortical dopamine function, but nobody really knows how this is any different from the modulation that occurs when you block 5-HT2. Latuda promotional material makes much of the fact that it has no effect on the muscarinic or histaminergic receptors.

Indeed, lurasidone causes very little weight gain (in line with its lack of antihistamine effects), but it does cause significant sedation, which—it’s speculated—may be a result of its effects on the 5-HT7 receptor. Lurasidone also antagonizes alpha-1 noradrenergic receptors, and there is a small incidence oforthostatic dizziness, especially early in treatment.

Therapeutic Effects
Lurasidone is, indeed, effective for the core symptoms of schizophrenia. The company submitted the results of four six-week placebo-controlled trials, using the PANSS score as the primary outcome variable. (The PANSS is the Positive and Negative Symptom Scale for schizophrenia, which rates patients on positive symptoms, negative symptoms, and—in this study—disorganized thought, hostility, and depression/anxiety.)

Patients were randomly assigned to 40 mg/day, 80 mg/day, and 120 mg/day dosages, and to placebo. Patients on lurasidone generally showed more improvement in their PANSS sores than those on placebo. All studies showed effectiveness of the 80 mg dose, but two out of three studies at 120 mg did not, no doubt explaining why FDA approval extends only up to 80 mg. (The percentages in table 1 do not seem to reflect the relative inferiority of the 120 mg dose because these are summaries of the three studies that tested this dose.) “Responders” are those with a decrease of at least 20% in the BPRS, 30% in the PANSS, or 2 on the CGI from baseline (Citrome L, Int J Clin Pract 65(2):189–210). Lurasidone Efficacy Results

Several other studies have been done with lurasidone in addition to the four studies that were submitted to the FDA—some published, most unpublished. One six-week trial of lurasidone 20 mg, 40 mg, and 80 mg was a failure, showing no difference from placebo. Another three-week trial of lurasidone at 120 mg showed similar efficacy to ziprasidone 80 mg twice daily (Cucchiaro J et al, Schizophr Bull 2009;35(suppl 1):342–343).

An unpublished one-year open-label study of 182 patients gives us a sense of the long term tolerability (or lack thereof ) of lurasidone. These patients were taking an average dose of 71 mg, and while most patients improved, the discontinuation rate was 56% over the course of the year—23% because of adverse effects, and 29% for lack of efficacy. Common side effects included serum prolactin increase (19%), and insomnia (18%), with EPS in 27% of patients. However, patients lost 3.3 pounds on average, and had small, nonsignificant decreases in cholesterol, triglycerides, and prolactin levels along with a nonsignificant increase in fasting glucose (Ogo HM et al, poster presented at: International Congress on Schizophrenia Research, 2011, Colorado Springs, CO).

Is Lurasidone “Pro-Cognitive”?
There’s usually a marketing angle accompanying new launches of drugs in crowded markets. In the case of lurasidone, this angle appears to be the idea that it may make patients a little smarter. However, thus far most of the supporting research has been done with animals, and the few human trials have not been conclusive.

If you give rats a brain toxin called MK-801, they will become forgetful, as measured by rat activities such as navigating mazes. In preclinical trials, lurasidone did a better job of reversing MK-801-induced memory impairment in rats than risperidone, olanzapine, or quetiapine (Enomoto T et al, Behav Brain Res 2008;186(2):197–207).

Also in rats, lurasidone was shown to upregulate BDNF(brain derived growth factor) in the prefrontal cortex (Fumagalli F et al, Int J Neuropsychopharmacol 2011:14(1):1–12). Since BDNF is decreased in both schizophrenia patients (Weickert CS et al, Mol Psychiatry 2003;8(6):592–610) and animal models of schizophrenia (Fumagalli F et al, Eur J Neurosci 2004;20(5):1348–1354; Roceri M et al, Biol Psychiatry 2004;55(7):708–714), a drug that can upregulate BDNF has theoretical appeal.

But what about lurasidone’s cognitive effects in humans? Thus far, two human studies have examined the question. One administered lurasidone 80 mg or placebo to 180 patients with schizophrenia for six weeks, and showed a small (-2.1 vs -0.5) but significant (p=0.0015) improvement in the cognitive subscale of the PANSS versus placebo (Nakamura M et al, J Clin Psychiatry 2009;70(6):829–836).

That sounds impressive, but the study did not compare lurasidone with other medications. Also, the cognitive subscale of PANSS does not really measure cognitive dysfunction per se, but rather thought patterns common in schizophrenia, such as stereotyped thinking, lack of abstract thinking, and lack of judgment and insight.

The other study in humans was a randomized double-blind three-week trial of lurasidone 120 mg (n=123) versus ziprasidone 80 mg twice daily (n=111) (Harvey PD et al, Schizophr Res 2011;127(1–3):188–194). Two outcome measures were used. One was a subset of tests from the MATRICS Consensus Cognitive Battery (MCCB), which is an interviewer-rated measure of cognitive function.

This showed a small but significant improvement in the lurasidone group, but not the ziprasidone group, which was consistent with a “practice effect.” It’s not clear why the ziprasidone group did not equally benefit from the practice effect, but several other antipsychotics have shown the effect in other studies.

The other outcome measure was the Schizophrenia Cognition Rating Scale (SCoRS). This is a structured 20-question interview of both the patient and an informant that is not susceptible to practice effects, because it measures functionality. The lurasidone group showed statistically significant improvements over three weeks on these measures, whereas the ziprasidone group did not. However, in direct comparisons between the two drugs, lurasidone did not show a statistical benefit over ziprasidone.

So—is lurasidone pro-cognitive, or isn’t it? The jury is still out. All antipsychotics appear to improve cognition to some degree, but the improvements are thought to be either artifacts of practice, or reflections of improvement in general psychotic symptoms (see Dr. Balt’s article in this issue for details). At this point, all we can say for sure is that in trials designed by Sunovion, lurasidone’s manufacturer, lurasidone appears slightly more pro-cognitive than one particular comparator, ziprasidone. Given the proven ability of companies to manipulate study design to make their drugs look better than their competitors’, we will have to await non-sponsored data before drawing clear conclusions.

Side Effects of Lurasidone
The most common side effects of lurasidone are somnolence, akathisia, nausea, parkinsonism, and fatigue, and are summarized in the table below. Lurasidone Side Effects

Some studies broke side effect frequency down by dose, others didn’t. We listed that information when it was available. At higher than the recommended dose (120 mg to 160 mg), anxiety, insomnia, agitation, and fatigue predominate. Dystonia and extrapyramidal side effects are dose-dependent, and are comparable to risperidone, olanzapine, and ziprasidone. There are no significant increases vs placebo in triglycerides, cholesterol, or fasting glucose (Newcomer J et al, poster presentation at: International Congress on Schizophrenia Research, 2011, Colorado Spring, CO). QTc prolongation is minimal (average 1.5 ms, as opposed to the 10 ms average increase seen in patients taking ziprasidone), with no patient showing more than a 50 ms increase, and there are no other observed changes in EKG, laboratory measures, or vital signs.

Pharmacokinetics
Like ziprasidone, lurasidone is one of those annoying drugs that you have to take with food, which doubles its absorption. In terms of drug interactions, lurasidone is metabolized by cytochrome P450 3A4. This means that 3A4 inhibitors, such as diltiazem (Cardizem), will increase lurasidone levels. The worst actor is ketoconazole (Nizoral), which raises lurasidone levels sevenfold, and is contraindicated. Rifampin (Rifadin), a 3A4 inducer, lowers levels by 85%, and is likewise contraindicated.

Comparisons with Other Antipsychotics

    Lurasidone advantages:
  • Once-daily dosing
  • Initial dose is therapeutic
  • Minimal weight gain
  • Minimal increase in lipids, cholesterol, and fasting glucose
  • Minimal QTc prolongation
    Lurasidone disadvantages:
  • Sedation
  • Akathisia and other EPS
  • No track record of safe use, therefore possibility of rare post-marketing side effects
  • No IM or sublingual formulation
  • No FDA indications (yet) for bipolar disorder
  • Expensive
  • Must be taken with food
  • Potential for 3A4 drug interactions
TCPR Verdict: 

TCPR Verdict: Lurasidone works as well as other second-generation antipsychotics, and its main side effects are EPS and sedation; it causes little weight gain or metabolic problems. It’s unclear whether it improves cognition more than other atypicals—so far there is no clear human evidence that it does. In clinical practice, you might lump lurasidone with the other atypicals that cause little weight gain, such as aripiprazole, ziprasidone, and asenapine. Whether you use it or not depends on your practice style. Some of us are early adopters, and others take a wait-and-see approach.