Antipsychotic disappointment

A LEADING Australian psychiatrist has labelled as “extremely disappointing” a US finding that a second-generation long-acting injectable drug to treat schizophrenia is no more efficacious than a first-generation drug.

Professor Ian Hickie, executive director of the Brain and Mind Institute, said the study comparing injectable paliperidone palmitate with injectable haloperidol decanoate demonstrated the lack of genuine progress in the treatment of schizophrenia.

The double-blind randomised clinical trial of 311 adults with schizophrenia or schizoaffective disorder, published in JAMA, found no difference in efficacy failure — defined, in part, as a psychiatric hospitalisation, a need for crisis stabilisation or a substantial increase in frequency of outpatient visits — between the antipsychotics. (1)

Patients were given monthly intramuscular injections of haloperidol decanoate (mean monthly dose, 67–83 mg) or paliperidone palmitate (mean monthly dose, 129–169 mg) for up to 24 months.

The researchers found that paliperidone was associated with a mean weight gain of 2.17 kg compared with haloperidol, which resulted in mean weight loss of 0.96 kg. Paliperidone was also associated with significant higher mean level of serum prolactin (34.56 µg/L v 15.41 µg/L in men and 75.19 µg/L v 26.84 µg/L in women). Haloperidol was associated with significantly larger increases in global ratings of akathisia (0.73 v 0.45).

Professor Hickie said while the results were not particularly surprising given the two drugs had basically the same mechanism — blocking dopamine receptors — it was disappointing to find that the money and effort invested in developing this line of pharmacotherapy had resulted in only very small advances.

An accompanying editorial in JAMA said the findings suggested that doctors should base drug selection for patients on anticipated side effects rather than efficacy. (2)

Professor Tim Lambert, professor of psychiatry at the University of Sydney’s Concord Clinical School, agreed that side effects should be the focus for prescribers.

“[The study is] really telling us that extrapyramidal side effects (EPS) are worse in the haloperidol group. Now, what’s more important: getting metabolic side effects or getting EPS”? he asked.

“EPS is potentially connected directly to irreversible brain changes when it gets to tardive dyskinesia whereas developing type 2 diabetes isn’t so clearly related to direct structural brain change”, he said.

Professor Hickie, who is also commissioner of the National Mental Health Commission, said the side effects of the older drugs were terrible.

“Those of us who have worked with the older drugs and the older injectables know the side effects — the akathisia, the parkinsonism, the motor restlessness”, he said, adding that this was why psychiatrists and patients had retreated from these drugs.

However, he said the newer drugs were not completely free of these side effects and had the additional issues of weight gain and potential metabolic complications.

“While [the newer drugs are] potentially somewhat better on the motor effects, there’s this [question] of do you pay an additional price of the weight gain and metabolic complications of the newer drugs — particularly in injectable form? It’s a very significant issue”, he said.

Professor Hickie said providing patients and carers with treatment alternatives was important. “But it does raise the much bigger question that we really desperately need new ways of coming at the problem that are more efficacious as well as more palatable at the consumer end.”

Professor Lambert said it was the effectiveness of long-acting antipsychotics that should be considered.

“You want a long-acting injection to be simple to use, effective, be able to allow the prescriber to control symptom fluctuations dynamically, not cause horrible side effects and work against classical psychotic symptoms at least as well as anything else”, Professor Lambert said.

He said when comparing all the different preparations of the long-acting injections, paliperidone appeared to be most successful, based on audits of prescribing frequency.

In April, the Therapeutic Goods Administration launched a review of paliperidone in response to reports from Japan that 17 deaths were associated with the drug. The review is ongoing. (3)

Professor Lambert said Japan’s prescribing culture was “unique” with simultaneous prescription of up to five antipsychotics common and different methods of collecting adverse outcome data.

However, he said the reports from Japan were “a signal” to keep up to date with postmarketing surveillance.

1. JAMA 2014; 311: 1978-1987
2. JAMA 2014; 311: 1973-1974
3. Medical Observer 2014; Online 11 April