Overview Taiwanese Journal of Psychiatry (Taipei) Vol. 31 No. 2 2017 • 115 • Developing Drugs for Negative Symptoms of Schizophrenia Chih-Min Liu, M.D., Ph. D.1,2 Negative symptoms in schizophrenia represent a clinically important target for drug development due to their profound effect on an individual’s ability to function normally. The lack of effective medications for this domain of psychopa- thology is a major unmet medical need in schizophrenia. Earlier clinical trials for negative symptoms have been criticized mixing primary and secondary negative symptoms as treatment target and lack of standard protocols for clinical trial de- sign. In the fi rst part, The author is reviewing the methodological issues on defi n- ing and measuring negative symptoms and on developing the consensus for clini- cal trial design for negative symptoms. Defi cit symptoms and persistent negative symptoms, instead of broadly defi ned negative symptoms, have been advocated as the treatment target of clinical trial. There were fi ve commonly used interview- based negative symptom scales with satisfactory psychometric profi les. The con- sensus has been achieved for the design of clinical trials for negative symptoms. In the second part, the treatment effi cacy of different class of drugs on negative symptoms is reviewed. Some second-generation antipsychotics, antidepressants, psychostimulants, glutamate pathway molecules, serotonin receptor antagonists, and anti-infl ammatory agents have modest effects on improving negative symp- toms than placebo. Although some statistically signifi cant effects on negative symptoms are evident, none has reached the threshold for clinically signifi cant. Several new molecules with potentials in treating negative symptoms are still in development. Key words: schizophrenia, negative symptoms, medication, clinical trials (Taiwanese Journal of Psychiatry [Taipei] 2017; 31: 115-27) Negative symptoms are substantially more resis- Introduction tant to current pharmacological treatments than positive symptoms [2]. With the exception of ami- The negative symptoms of schizophrenia sulpride [3] in some European countries, no phar- have been receiving much clinical attention for a macological agents have been approved for the long time because of its signifi cant correlation treatment of negative symptoms. The National with poor functional and long-term outcomes [1]. Institute of Mental Health (NIMH) Measurement 1 Department of Psychiatry, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan 2 Graduate Institute of Brain and Mind Sciences, National Taiwan University College of Medicine, Taipei, Taiwan Received: May 22, 2017; accepted: May 23,2017 *Corresponding author. No. 1, Changde Street, Taipei 100, Taiwan E-mail: Chih-Min Liu <[email protected]> • 116 • Drugs for Negative Symptoms of Schizophrenia and Treatment Research to Improve Cognition in current improvement of positive, depressive, and/ Schizophrenia (MATRICS) has turned its atten- or extrapyramidal symptoms. These are the major tion to negative symptoms [4]. The United States sources of secondary negative symptoms, and Food and Drug Administration (FDA) has en- other sources of secondary symptoms are usually dorsed negative symptoms of schizophrenia as a not even assessed. Thus, the use of broadly de- legitimate drug target for a labeling indication and fi ned negative symptoms as treatment target is un- has offered guidelines for development [5]. The likely to lead to the development of effective European Medicines Agency has also offered treatments for those negative symptoms, which guidelines for claiming effects on negative persist during clinical stability and are associated symptoms. with impaired rôle function performance [10]. There are two alternative approaches for de- Methodological Issues fi ning negative symptoms in the context of clini- cal trials. The fi rst approach is termed as “defi cit Defi nition of negative symptoms symptoms,” which restrict negative symptoms to Negative symptoms of schizophrenia contain primary enduring negative symptoms, which re- the following features: affective fl attening, alogia, quired clinicians to rule out any secondary causes avolition, asociality, and anhedonia [4]. Factor of negative symptoms and confi rm the persistence analyses have isolated two separate but related of these symptoms during clinical stable period subdomains, diminished expression (e.g., affec- [11]. The second approach is termed as “persistent tive fl attening), and amotivation (e.g., avolition/ negative symptoms” to include both primary neg- apathy) [6]. ative symptoms and those secondary negative Heterogeneous clinical manifestations exist symptoms, which are persistent presented during with different causes and longitudinal stability. clinical stable period and have not responded to Considering their causes and longitudinal stabili- appropriate treatments [12]. Both those approach- ty, secondary negative symptoms are referred to es have advantages over negative symptoms negative symptoms occurring presumably caused broadly defi ned for isolating those negative symp- by positive symptoms, affective symptoms, medi- toms that are the most relevant treatment target. cation side effects, environmental deprivation, or Researchers proposed that primary enduring other treatment- and illness-related factors [7], negative symptoms, named as defi cit symptoms, while primary enduring negative symptoms refer- may defi ne a separate disease entity, i.e., the defi - ring to the ones, from which other secondary cit syndrome, which is characterized by a distinct causes have been ruled out, persistently present- etiopathophysiology [13]. The defi cit form of ing for a long duration and with a stable degree of schizophrenia is defi ned by the following criteria severity. The term broadly defi ned negative symp- [11]: toms are negative symptoms without considering ‧ At least 2 of the following 6 features must be their causes, longitudinal stability, or duration. present and of a clinically signifi cant severity: Earlier studies showed negative symptoms im- (A) restricted affect, (B) diminished emotional prove during fi rst- and second-generation antipsy- range, (C) poverty of speech, (D) curbing of in- chotic drug treatment [8, 9]. But in most of these terest, (E) diminished sense of purpose, and (F) studies, this effect has been correlated with con- diminished social drive. Liu CM • 117 • ‧ Two or more of these features must have been ‧ No (or low level of) extrapyramidal symptoms present for the preceding 12 months and must on an accepted and validated rating scale. have always been present during periods of ‧ Demonstrated clinical stability for an extended clinical stability (including chronic psychotic period of time prior to the start of the study. states). Persistent negative symptoms differ from ‧ Two or more of these enduring features are also broadly defi ned negative symptoms by the re- idiopathic, i.e., not secondary to factors other quirement for persistence of the symptoms. than the disease process. Such factors include Persistent negative symptoms differ from defi cit (A) anxiety, (B) drug effects (especially, extra- symptoms in several aspects: pyramidal side effects), (C) suspiciousness, (D) ‧ The defi nition of duration: defi cit symptoms formal thought disorder, (E) hallucinations or need to be present for at least 12 months, delusion, (F) mental retardation, and (G) whereas persistent negative symptoms may be depression. present for any predefi ned time period, though ‧ The patient meets the Diagnostic and Statistical usually a minimum of 6 months. Manual of Mental Disorders, Fourth Edition ‧ Their severity is defi ned by a clinical need for criteria for schizophrenia. therapeutic intervention. The most challenging issue for the defi cit ‧ They are defi ned through a number of temporal syndrome is that information about the longitudi- and scalar criteria easily applicable within the nal course of the symptoms required to make the clinical trial context. primary/secondary distinction may not always be In light of the estimated 15% - 20% preva- readily available. In addition, the differentiation lence of the defi cit syndrome, the prevalence of of primary and secondary negative symptoms re- persistent negative symptoms is probably higher quires a level of clinical sophistication above and because persistent negative symptoms also include beyond what is usually available in clinical raters. unresponsive secondary negative symptoms [12]. Also, the prevalence of defi cit syndrome of schizophrenia has been estimated only 15% - 20% Measurement of negative symptoms of patients [4, 14], which cause diffi culty recruit- Instruments for measuring negative symp- ing adequate number of patients for clinical trial toms suitable for use in the clinical trial should and limited the generalizability of the drugs. have the following characteristics: (A) the scale The concept of persistent negative symptoms should measure all of the domains of negative represents a broader concept than the defi cit syn- symptoms and not be contaminated by other do- drome. The criteria of persistent negative symp- mains; (B) it should be sensitive to change; (C) toms [12] are described: the instrument should demonstrate good reliabili- ‧ At least moderate severity of negative symp- ty in the settings where the trials will be carried toms, defi ned on an accepted and validated rat- out; (D) it should be relatively brief; and (E) it ing scale. should be an instrument