Evidence-Based Reviews

Treating negative symptoms of schizophrenia

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Seeking new pharmacologic options

The years since the PORT review have been filled with initial promise, a series of bitter disappointments, and a renewed spark of hope in the quest to treat negative symptoms in schizophrenia.

Compounds that have been abandoned. Since PORT, researchers have evaluated 5 major compounds that mainly targeted cognition and negative symptoms in patients with schizophrenia (Box9-17). Unfortunately, 4 of them failed to provide significant superiority over placebo, and 1 was withdrawn due to safety concerns.


Treatments for negative symptoms: 5 Drugs that didn’t pan out

Since the Schizophrenia Patient Outcomes Research Team (PORT) treatment recommendations were published in 2010, many compounds have been investigated for treating negative symptoms of schizophrenia. Based on the findings of early research, further development of 5 of these has been abandoned.

Encenicline and TC-56199 were both α-7 nicotinic acetylcholine receptor agonists10; bitopertin and AMG 74711 were glycine reuptake inhibitors12; and pomaglumetad methionil13 was an amino acid analog drug that acts as a highly selective agonist for the metabotropic glutamate receptor.

Encenicline showed a treatment effect on negative symptoms in an add-on phase II study,14 but not in 2 subsequent phase III trials (NCT01716975, NCT01714661). TC-5619 showed a treatment effect in a 12-week phase II study of participants with persistent negative symptoms,15 but then failed in a subsequent study.9 Bitopertin showed a treatment effect on negative symptoms in 1 clinical trial,16 but the results were not replicated in a subsequent large multi-center trial.17 The AMG 747 development program was halted due to safety concerns.11 Finally, pomaglumetad methionil failed to meet its primary endpoint in a study of prominent negative symptoms and to show a treatment effect on psychotic symptoms in 2 pivotal phase III trials.13

Initial favorable results. Registered, robust trials of other compounds have had some initial favorable results that need to be replicated. These agents include:

  • MIN-101 is a novel cyclic amide derivative.18 In a phase IIb 12-week study of MIN-101 monotherapy (32 mg, n = 78; 64 mg, n = 83) vs placebo (n = 83), both dose groups had significantly more improvement on the Positive and Negative Syndrome Scale (PANSS) negative factor score, which was the primary outcome measure, than placebo (32 mg/d; effect size = .45, P < .02, 64 mg/d; effect size = .57, P < .004) as well as on PANSS negative symptom score and other measures of negative symptoms.18
  • Cariprazine is a D2 and D3 receptor partial agonist with high selectivity towards the D3 receptor19
  • Minocycline is a broad-spectrum tetracyclic antibiotic displaying neuroprotective properties18,20,21
  • Raloxifene is a selective estrogen receptor modulator for postmenopausal women22,23
  • Pimavanserin, which was FDA-approved in 2016 for the treatment of Parkinson’s disease psychosis, is being tested in a large trial for adjunctive treatment of patients with negative symptoms of schizophrenia. This medication is a nondopaminergic antipsychotic that acts as a selective serotonin inverse agonist that preferentially targets 5-HT2A receptors while avoiding activity at common targets such as dopamine.24

All of these compounds except MIN-101 are currently available in the U.S. but have not been approved for the treatment of negative symptoms in patients with schizophrenia. MIN-101 is in phase III testing (NCT03397134).

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