Background: Both neurocognitive impairments and negative symptoms of schizophrenia (NSS) are believed related to mesocortical dopaminergic hypofunction. This analysis examined the hypothesis that the dopamine agonist, d-amphetamine prodrug, lisdexamfetamine dimesylate (LDX), would improve neurocognition along with NSS in adults with clinically stable schizophrenia maintained on atypical antipsychotics. Methods: Outpatients with schizophrenia (>2 years) and predominant NSS, on antipsychotics (>12 weeks), underwent 10-week open-label (OL) LDX augmentation (20-70mg/d). Eligible participants (any SANS-18 improvement at week 10) entered 4-week, double-blind, placebo-controlled randomized withdrawal (RW). Efficacy measures included SANS-18 (primary), Brief Assessment of Cognition in Schizophrenia-Symbol Coding Subtest (BACS-SC), Hopkins Verbal Learning Test-Revised, Immediate Recall (HVLT-R), and Letter Number Span Test (LNS). Safety evaluations included treatment-emergent adverse events (TEAEs). Results: In 92 participants receiving OL LDX, SANS-18 mean change (95% CI; weeks 0-10 OL, LOCF) was -12.9 (-15.0, -10.8) (P<.0001). Mean change (95% CI) in BACS-SC T-score was 2.0 (0.1, 3.9) (P=.0369); mean change in HVLT-R and LNS T-scores were 0.4 (-1.1, 2.0) and 1.3 (-0.4, 3.0), respectively (both P=NS). During RW, no significant differences were noted (LDX vs placebo) for these outcomes. In the OL phase, 56/92 (60.9%) reported TEAEs; 3/92 (3.3%) reported serious TEAEs. Conclusions: LDX improved NSS without worsening positive symptoms of schizophrenia. This was accompanied by small but significant improvements in BACS-SC. Confirmation with larger placebo-controlled trials, various doses, and additional cognitive measures is warranted given the significant unmet need for treating negative and cognitive symptoms in schizophrenia.
The etiology of schizophrenia is poorly understood and two principle hypotheses have dominated the field. Firstly, that subcortical dopamine function is enhanced while cortical dopamine function is reduced and secondly, that cortical glutamate systems are dysfunctional. It is also widely accepted that currently used antipsychotics have essentially no impact on cognitive deficits and persistent negative symptoms in schizophrenia. Reduced dopamine transmission via dopamine D1 receptors in the prefrontal cortex has been hypothesized to be involved in the aetiology of these symptom domains and enhancing cortical dopamine transmission within an optimal window has been suggested to be potentially beneficial. In these pre-clinical studies we have determined that combined administration of the d-amphetamine pro-drug, lisdexamfetamine and the atypical antipsychotic olanzapine increased dopamine efflux in the rat prefrontal cortex and nucleus accumbens to an extent greater than either drug given separately without affecting olanzapine’s ability to block striatal dopamine D2 receptors which is important for its antipsychotic activity. Furthermore, in an established rodent model used to compare the subjective effects of novel compounds the ability of lisdexamfetamine to generalize to a d-amphetamine cue was dose-dependently attenuated when co-administered with olanzapine suggesting that lisdexamfetamine may produce less marked subjective effects when administered adjunctively with olanzapine
Pregnenolone (PREG) and L-Theanine (LT) have shown ameliorative effects on various schizophrenia symptoms. This is the first study to evaluate the efficacy and safety of augmentation of antipsychotic treatment among patients with chronic schizophrenia or schizoaffective disorder with PREG – LT.
Double-blind, placebo-controlled trial of PREG – LT or placebo augmentation was conducted for 8 weeks with 40 chronic DSM-IV schizophrenia and schizoaffective disorder patients with suboptimal response to antipsychotics. Oral PREG (50 mg/day) with LT (400 mg/day) or placebo were added to a stable regimen of antipsychotic medication from March 2011 to October 2013. The participants were rated using the Scale for the Assessment of Negative Symptoms (SANS), Hamilton Scale for Anxiety (HAM-A), and Positive and Negative Syndrome Scale (PANSS) scales bi-weekly. The decrease of SANS and HAM-A scores were the co-primary outcomes. Secondary outcomes included assessments of general functioning and side effects.
Negative symptoms such as blunted affect, alogia, and anhedonia (SANS) were found to be significantly improved, with moderate effect sizes among patients who received PREG-LT, in comparison with the placebo group. Add-on PREG-LT also significantly associated with a reduction of anxiety scores such as anxious mood, tension, and cardiovascular symptoms (HAM-A), and elevation of general functioning (GAF). Positive symptoms, antipsychotic agents, concomitant drugs, and illness duration did not associate significantly with effect of PREG-LT augmentation. PREG-LT was well-tolerated.
Pregnenolone with L-Theanine augmentation may offer a new therapeutic strategy for treatment of negative and anxiety symptoms in schizophrenia and schizoaffective disorder. Further studies are warranted.
Overwhelming research evidence suggests that the negative symptoms of schizophrenia (NSS) contribute more to impaired quality of life and poor functioning than positive symptoms, and that NSS, including affective flattening, alogia and avolition are present in at least one-fifth of patients diagnosed with schizophrenia. Despite this, management of NSS continues to be a major clinical unmet need as treatment with current antipsychotic medication seems to reach at best modest efficacy.
A critical review of the current pharmacological, non-pharmacological and psychosocial treatments available for NSS is presented here, using data retrieved from the MEDLINE/PUBMED, the Cochrane Database of Systematic Reviews and the ClinicalTrials.gov databases. An early and accurate diagnosis using selective scales is essential for documentation and monitoring of change in NSS according to treatment response. Typical and atypical antipsychotic drugs, showed modest efficacy in managing NSS. Conflicting results were obtained with the use of glycinergic neuromodulators, anticholinergics, antidepressants, anticonvulsants, psychostimulants, modafinil and 5-HT3 receptor antagonists. Moreover, non-pharmacological therapies including psychological therapies have failed to address NSS effectively.
At present, it appears that the best effective approach for clinical management of NSS is achieved by complementing drug therapy with psychosocial therapies. Continuing basic and clinical research for the understanding of the genetic, behavioral and neural basis of NSS should yield novel pharmacotherapies with superior efficacy, tolerability and long-term maintenance for improved treatment of NSS.
Antipsychotic drugs and negative symptoms
Tandon and Jibson (2002): antipsychotics seem to show some improvement on NSS through their effect on positive symptoms
Lieberman et al. (2005): perphenazine was found similar in effectiveness to newer medications (with the exception of olanzapine) and there were no significant advantages in efficacy for any of the atypical antipsychotics with regards to negative symptoms
Jones et al. (2006): The Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS), where 1227 people with schizophrenia were randomised to either a typical (chlorpromazine, flupenthixol, haloperidol, loxapine, sulpiride, zuclopenthixol) or atypical drug other than clozapine (amisulpride, olanzapine, quetiapine or risperidone) found no significant differences for either class of drug in symptom reduction
Stip and Tourjman (2010): aripiprazole was associated with improvement in both positive and negative symptoms and with a benign safety profile
Darbá et al. (2011) concluded that atypical antipsychotics are significantly better than typicals, with amisulpride and ziprasidone showing the highest effect sizes.
Amr et al. (2013): quetiapine (200mg/d) was found to be more effective than haloperidol (5mg/d) in decreasing NSS but not in decreasing general psychopathology.
Pilla Reddy et al. (2013) found that positive symptoms of schizophrenia responded well to all antipsychotics and olanzapine showed a better effect towards negative symptoms than the other atypical antipsychotics and haloperidol.
Khanna and colleagues (2014): aripiprazole was similar in effectiveness with risperidone, better than ziprasidone and not as effective as olanzapine but with better tolerability and fewer side effects
Shafti and Gilanipoor (2014): In a 12-week double-blind clinical trial, olanzapine displayed superior efficacy with respect to negative symptoms in comparison with the risperidone.
CATIE study concluded that “each drug might be most useful in particular situations depending on several factors such as illness course and extrapyramidal symptoms.”
Only one-third of patients respond well to clozapine. Although clozapine augmentation is common practice, meta-analytic studies examining antipsychotic polypharmacy suggested a small effect in managing treatment resistant schizophrenia (Taylor et al., 2009, 2012)
Antidepressant augmentation of antipsychotics:
“Due to similarities between negative and depressive symptoms in schizophrenia patients and the effectiveness of antidepressants in treating depressive symptoms in schizophrenia, treatment combination of antipsychotics with selective serotonin reuptake inhibitors (SSRI) has repeatedly been suggested as a promising strategy in NSS (Zullino et al., 2002). Indeed there are several clinical guidelines recommending the antidepressants in addition to antipsychotic treatment for schizophrenia patients with persisting negative symptoms”
Spina and colleagues (1994): addition of fluoxetine (20 mg/day) to typical antipsychotics gradually improved negative symptoms.
Berk et al. (2001): mirtazapine combined with haloperidol had a significant positive impact on improving NSS
Rummel-Kluge and colleagues (2006): combination therapy showed significant clinical improvement in NSS compared to patients who received only antipsychotic medication
A meta-analysis by Singh and colleagues (2010): fluoxetine, trazodone and ritanserin produced a statistically significant effect whereas mirtazapine, reboxetine, mianserin, fluvoxamine, sertraline, paroxetine and citalopram failed to provide similar outcomes (number of RCTs included in the meta-analysis was very small and so the actual effect size of each individual antidepressant might have lost great power). They concluded combined antipsychotic/antidepressant therapy is more effective in treating NSS than antipsychotics alone
Cho et al. (2011): when mirtazapine was used as an add-on therapy to risperidone, the mirtazapine group exhibited a statistically significant improvement in negative symptoms.
Caforio et al. (2013): olanzapine/mirtazapine treatment was more effective than olanzapine alone in improving NSS
Stryjer and colleagues (2013): a significant improvement in the total PANSS scores after administering escitalopram as adjunctive therapy to antipsychotics
Tsai et al. (2014) found the combination of escitalopram with aripripazole to be effective in improving NSS.
“…most studies point to the importance of including an antidepressant agent for improving treatment of NSS, this finding has not been replicated by other studies that found no beneficiary effect of antidepressants in reducing NSS”
“…it was hypothesized that hypofunction of the NMDA receptor contributes to the development of schizophrenia symptoms and that the use of direct augmentation of glycine receptor agonists such as glycine and D-cycloserine, which indirectly stimulate NMDA receptors, would prove effective in managing NSS. Buchanan et al. (2007) conducted a sixteen-week double-blind, placebo-controlled trial in 157 patients diagnosed with schizophrenia and schizoaffective disorder and treated with glycine or D-cycloserine as adjunctive therapies to antipsychotic drugs. Findings revealed that the two glutamanergic agents were ineffective in reducing NSS. Lane et al., (2005) also reported no significant association between D-serine and NSS in a six-week trial on 65 individuals with schizophrenia, but reported beneficial effects from the use of sarcosine (N-methylglycine) as adjunctive therapy to risperidone. This finding replicated earlier findings (Tsai et al. 2004). Weiser and colleagues (2012) conducted a 195-patient, multicenter, double-blind, randomized, placebo-controlled, 16-week trial of d-serine 2 gm/day as add-on treatment to antipsychotics. Participants receiving d-serine showed an improvement on the SANS scores however, the authors failed to report a significant difference between augmentation with d-serine and placebo. Bitopertin (RG1678; RO-4917838) is a glycine reuptake inhibitor, which was under development by Roche as an adjunctive therapy to antipsychotics for the treatment of persistent NSS. However, preliminary results of two of six phase III studies have been disappointing as they did not meet their primary endpoints. In a press release, Roche announced that the investigational drug failed to significantly reduce NSS as measured by PANSS after 24 weeks compared to placebo, and the program was halted. Another selective glycine uptake inhibitor of type 1 glycine transporter, Org 25935, did not differ significantly when compared to placebo in the reduction of NSS as measured with the SANS and the PANSS (Schoemaker et al., 2014). The latter findings raised questions about the therapeutic potential of glycinergic neuromodulation in treatment of NSS (Kingwell, 2014).”
“…memantine, a weak NMDA receptor antagonist, has been investigated in various studies that aimed to test its efficacy in treating negative symptoms in schizophrenia. De Lucena et al. (2009) conducted a double-blind, placebo-controlled study in patients with refractory schizophrenia who received either 20 mg/d of memantine (n = 10) or placebo (n = 11), in addition to clozapine, for 12 weeks. Data showed that memantine was associated with significant improvement in reducing NSS as measured with the BPRS. In a more recent study, Rezaei et al. (2013) administered memantine (20 mg) as add-on therapy to risperidone in 38 patients with schizophrenia, for a period of 8 weeks. The authors reported that the negative symptoms were significantly improved in memantine-treated patients vs. placebo when assessed with PANSS.”
“Choi and colleagues (2013) conducted a meta-analysis, consisting of 26 double-blind, placebo-controlled studies, to examine the efficacy of cholinergic, glutamatergic and serotonergic agents as adjunctive pharmacotherapies to treat negative symptoms and cognitive deficits in schizophrenia. Results showed that medications targeting acetylcholinesterase, such as the acetylcholinesterase inhibitors donepezil and galantamine, had a moderate effect size (d = 0.58) as add on therapy to antipsychotics for the improvement of NSS.”
“…adjunctive administration of anticonvulsant drugs, such as carbamazepine, topiramate and lamotrigine, has been proposed as a useful treatment strategy for treatment resistant schizophrenia patients but remains controversial. Augmentation with lamotrigine as adjunctive medication specifically to clozapine, has been reported to decrease NSS. Premkumar and Pick (2006) conducted a meta-analysis of 5 double-blind, placebo-controlled trials to evaluate the efficacy of lamotrigine as add on therapy to various antipsychotics including clozapine. Findings revealed a significant decrease in the negative symptom scores, assessed with PANSS, from baseline. On the other hand, Goff and colleagues (2007) failed to replicate these results. The authors conducted a randomized, double-blind, parallel group study, to examine the effect of lamotrigine augmentation on schizophrenia symptomatology. Results showed that after 12 weeks, negative symptoms assessed by the SANS, improved more with placebo than lamotrigine.
Similarly, augmentation with topiramate to antipsychotic medication has produced controversial results. Tiihonen et al. (2005) examined whether topiramate is more effective than placebo in reducing symptoms in schizophrenia. The authors recruited twenty-six patients with treatment resistant schizophrenia and added 300 mg/day of topiramate to the patients’ ongoing treatment for a period of 12 weeks. Data revealed that topiramate was effective in reducing overall psychopathology but did not reach significance in reducing negative and positive symptoms.”
Anti-inflammatory agents are covered:
“Pregnenolone is an endogenous neurosteroid in the central nervous system (CNS). It is thought to improve N-menthyl-D-aspartate (NMDA) receptor function and GABA receptor responsiveness (Marx et al., 2011). Despite many limitations, clinical trial data utilizing pregnenolone seems promising. Marx and colleagues (2009) found that pregnenolone (500 m/d) used as add-on therapy to antipsychotics for 8 weeks significantly decreased negative symptoms as measured by SANS. Further support derives from a recent study conducted by Ritsner and colleagues (2014). They reported that pregnenolone significantly reduced NSS, in particular especially avolition, blunted affect and anhedonia. The effect of pregnenolone was even greater when patients were not treated with concomitant mood stabilizers.”
Aspirin: “Laan et al. (2010) conducted a double blind, placebo controlled study recruiting 70 patients with moderate to severe schizophrenia. Patients were randomized to adjunct treatment with aspirin 1000 mg/d or placebo and were treated for three months. Positive and negative symptoms were assessed by PANSS. Blood samples for immunological measurements were taken and cytokines were analysed using ELISA-assays. They found that the more altered the patient’s immune system was, the more beneficiary proved to be add on therapy with aspirin. They reported a statistically significant decrease in positive symptoms and a decrease to a lesser extent in the NSS.”
“The therapeutic benefit of COX-2 inhibitors on the reduction of symptoms in schizophrenia has been investigated by Muller and colleagues (2010). The authors conducted a double-blind, placebo-controlled, randomized trial of celecoxib augmentation (400 mg) to amisulpride treatment in 49 first episode schizophrenia patients. Compared to the group with amisulpride plus placebo, the treatment group showed significant reduction (p = 0.03) in the NSS as assessed with the PANSS. Chaudhry et al. (ClinicalTrials.gov NCT01602029, 2013) are currently studying the effect of adjunct therapy with ondansetron and/or simvastatin on negative symptoms of schizophrenia. They conduct a double blind placebo controlled study where a total of 216 patients will be recruited over a period of three years from both inpatient and outpatient settings and will be treated for six months. Based on past research findings of the efficacy of COX-2 inhibitors in managing NSS their main assumption is that addition of ondansetron and/or simvastatin to standard treatment in patients with schizophrenia will show a significant improvement in the reduction of their NSS”
“Minocycline (INN) is a broad-spectrum tetracycline antibiotic and anti-inflammatory drug and its use in the treatment of NSS has been encouraged by evidence derived from animal models (Monte et al., 2013). Khodaie-Ardakani and colleagues (2014) examined the efficacy of minocycline (200 mg/d) on NSS as an add-on therapy to risperidone on 38 patients with stable schizophrenia over a course of 8 weeks. Results revealed a clinically significant improvement in NSS in patients treated with combined therapy (p < 0.001). Further support comes from the study of Liu et al. (2014) who tested the efficacy of minocycline as adjunctive therapy to risperidone in 92 patients with early stages of schizophrenia. NSS were assessed by administering PANSS and SANS, and both scales showed significant score reductions (p < 0.001) after 16 weeks of treatment. Chaudhry et al. (2012) conducted a double-blind, placebo controlled study to examine the efficacy of minocycline in reducing negative symptoms in early schizophrenia. NSS assessed with PANSS were significantly reduced compared to placebo after 1 year of co-administering minocycline with antipsychotics. The authors pointed out the beneficial effect of minocycline but debated the exact mechanism of action of minocycline (i.e. anti-inflammatory, neuroprotective or other) which remains under investigation. Further support comes from a study by Levkovitz et al. (2010), where 72 patients with early phase schizophrenia showed reductions in NSS as assessed with the SANS after minocycline (200 mg/day) was added to their standard medical treatment for a period of twenty-two weeks. Miyoka and colleagues (2008) conducted an off-label clinical trial study in 22 patients with treatment resistant schizophrenia. Minocycline augmentation lasted 8 weeks and NSS were measured with PANSS at baseline, 4 weeks and 8 weeks. The authors reported profound changes in the negative symptom scores (55.8% and 57.2% change from baseline at 4 and 8 weeks respectively).”
“… N-acetylcysteine (NAC) [has] been investigated in several clinical trials showing reduction of schizophrenia symptoms including negative symptoms such as apathy and motivation. Farokhnia et al. (2013) conducted a double-blind, placebo controlled, parallel-group study with a total sample of 42 patients with schizophrenia who scored 20 points or higher in the negative symptoms subscale of PANSS. After 8 weeks of add-on of high doses of NAC (2gm/day) to risperidone, a significant decrease in NSS was measured but not in the positive symptoms or general psychopathology.”
“Omega-3 fatty acids are polyunsaturated fatty acids with various important biological roles including scavenging of toxic free radicals. Past research findings suggest that oxidative stress and generation of toxic free radicals exist in schizophrenia (Mahadik et al., 2006; Perez-Neri et al., 2006). Oxidative damage of the brain has long been associated with reduction of polyunsaturated fatty acids (PUFA) membrane in the brain (Mahadik et al., 2001) and therefore intake of essential fatty acids, especially omega-3 and omega-6, which suggested as a possible solution to damaged membrane structures (Mazza et al., 2007). Further support for the role of polyunsaturated fatty acid deficits in schizophrenia comes from a clinical trial study conducted by Sethom et al. (2010). After measuring the level of PUFAs at baseline, the authors administered typical antipsychotic medication to 36 drug free patients for a period of 3 months. Results revealed that PUFA deficiencies are associated with both negative and positive symptoms. Joy and colleagues (2006) conducted a meta-analysis of five studies, which examined the effect of PUFAs in schizophrenia symptoms. They reported statistically significant but not clinically meaningful reduction in the PANSS scores”
Psychostimulants and wake-promoting agents:
“…despite a number of medicinally important pharmacological effects, the therapeutic use of psychostimulants is limited because of their abuse liability and the induction of psychosis following long term use. Serotonin 5-HT1A receptor agonists can inhibit amphetamine and apomorphine-induced psychosis hence co-administration of 5-HT1A agonists may help prolong any therapeutic use of psychostimulants. Preclinical and clinical studies are warranted to evaluate the effects of co-administration of 5-HT1A agonists on potential therapeutic profile of psychostimulants in the treatment of schizophrenia (Haleem, 2013).
Lindenmayer et al. (2013) conducted a literature review to examine the efficacy of various psychostimulant agents as add-on therapy to antipsychotics in managing negative symptoms. Findings revealed that DA agonists may improve NSS, partly due to their ability to stimulate mesocortical pathways, without exacerbating positive symptoms in patients with stable schizophrenia. The authors pointed out that larger controlled clinical trials are needed to further investigate the impact of psychostimulants in NSS. A recent open label study conducted by Lasser and colleagues (2013)examined the efficacy of lisdexamfetamine dimesylate (LDX), a d-amphetamine prodrug of the phenethylamine and amphetamine classes, as adjunctive therapy to antipsychotics in an open label clinical trial over a period of four weeks, in a sample of 69 patients with stable schizophrenia and predominant negative symptoms. Data analysis showed that LDX appeared to be associated with significant improvements in NSS as measured with the SANS scale and the PANSS, though these findings require further validation (Hutson et al., 2014).”
“…Arbabi et al. (2012) reported that modafinil (200 mg/day) as an adjunct therapy to risperidone was beneficial in managing negative symptoms and cognitive deficits of schizophrenia. These results are in accordance with earlier findings (Peloian and Pierre, 2008).”
“Armodafinil, the R-isomer of modafinil, is a non-amphetamine, wakefulness promoting medication. Kane and colleagues (2012) investigated the efficacy and tolerability of adjunctive armodafinil for the treatment of negative symptoms. They conducted a parallel-group, 24-week study, where patients with schizophrenia received one of 3 doses of once-daily armodafinil (150 mg, 200 mg, or 250 mg) or placebo, adjunctive to oral olanzapine, risperidone, or paliperidone for ≥ 6 weeks. Negative symptoms, measured with the PANSS, did not benefit from armodafinil augmentation when compared to placebo.”
“A growing body of evidence illustrates that 5-HT3 receptor antagonist drugs may be beneficial in the treatment of NSS. Tropisetron, ondasetron and granisetron are traditionally used as anti-emetic drugs for chemotherapy-induced and postoperative emesis. Noroozian et al. (2013) assessed the efficacy of tropisetron as adjunctive therapy to risperidone in treating NSS, in a sample of 40 patients with chronic, stable schizophrenia during an 8-week placebo-controlled trial. Tropisetron resulted in greater improvement of negative symptoms as assessed with the PANSS. Bennett and Vila (2010) reviewed 6 clinical trials that evaluated ondansetron for the treatment of schizophrenia and reported that ondansetron may be effective as an adjunct to antipsychotics for the treatment of NSS. Finally, a double-blind, randomized, placebo-controlled study with 38 patients with stable schizophrenia evaluated the effects of combined granisetron/risperidone on NSS for a period of 8 weeks. The granisetron/risperidone group showed statistically significant improvement in NSS compared to the placebo/risperidone group”
“The diagnosis of schizophrenia has devastating consequences for family members on emotional, social and economic levels. It is important to educate families about the nature of the disorder, its prognosis and its multi-symptoms including negative symptoms. Family members are often frightened and confused by the patient’s strange new beliefs or behaviors, decreased energy levels and loss of motivation (Song et al., 2014). Families and caregivers become more supportive and less critical towards the patient when they realize that amotivation and anhedonia are symptoms of the illness rather than behaviors reflecting the individual’s character (Velligan and Alphs, 2014). Indeed, expressed emotion (EE) which refers to the caregivers’ attitudes towards a person with a mental disorder, has been found to be one the most robust predictors of patients’ relapse in schizophrenia (Amaresha and Venkatasubramanian, 2012) and poor quality of life (Philips et al., 2002). Moreover, most often families do not know how best to respond to these changes and need guidance and direction. It becomes vital therefore, that family members should receive psychoeducation as early as possible following diagnosis (Sin and Norman, 2013).
The goal of the psychoeducational approach is to persuade and teach family members of a schizophrenia patient that the way they will behave towards the patient may facilitate recovery by compensating for deficits and sensitivities specific to the disorder.”
Cognitive Behavioral Therapy CBT:
“There is a large body of scientific evidence supporting the role of CBT in treating NSS and improving functional outcomes and quality of life.”
“…lower negative symptoms significantly predicted higher patient and therapist rated alliance. The authors concluded that negative symptoms might be a barrier to the development of therapeutic alliance and therefore influence the therapeutic outcome. Jones et al. (2012) conducted meta-analyses of 20 randomized trials to examine the efficacy of CBT (described as a talk/active therapy) on the reduction of symptoms, relapse and rehospitalisation, function and quality of life compared to non-active interventions such as supportive therapy. Results revealed some long-term effect in the reduction of affective symptoms. Overall, findings did not favour a particular type of therapy in terms of social function or quality of life.”
“Art therapy (art, music, body movement, dance and drama therapy) is a form of psychotherapy to manage the negative symptoms of schizophrenia as adjunctive therapy to antipsychotics. Its nonverbal aspect is thought to help people express their thoughts and feelings in a no-destructive way and therefore offers the potential of improving patients’ quality of life and enhancing their clinical outcome by reducing the negative symptoms of the disorder.”
Repetitive transcranial magnetic stimulation (rTMS)
Electroconvulsive therapy (ECT)
The Role of Genes
Future directions on treating negative symptoms in schizophrenia
“Pharmacological treatments seem to have little impact on negative symptoms. In recent years, the recovery in mental health relies heavily on the optimum standard and quality of life. Psychosocial interventions are therefore, important components in the management of schizophrenia. The selection of appropriate psychosocial treatment should be guided by the individual circumstances of each patient; the severity of their symptoms, their needs and their social context.”
“New medications are being developed to focus on targets other than or in combination to the dopaminergic system in order to efficiently reduce globally the symptoms of schizophrenia. Furthermore, the role of pharmacogenomics is growing in an effort to help determine which medical treatment is appropriate for each individual, based on their genetic makeup. Clinicians have started putting more emphasis on managing the negative symptoms of the disorder, as it is by now well established, that they account for most of the reported impaired functioning and low quality of life.”
Antagonists of N-methyl-D-aspartate-type glutamate receptors (NMDAR) induce symptoms that closely resemble those of schizophrenia, including negative symptoms. D-serine is a naturally occurring NMDAR modulator that reverses the effects of NMDAR antagonists in animal models of schizophrenia. D-serine effects have been assessed previously for treatment of established schizophrenia, but not in the early stages of the disorder. We aimed to assess effects of D-serine on negative symptoms in at risk individuals.
We did a double-blind, placebo-controlled, parallel-group randomised clinical trial at four academic US centres. Individuals were eligible for inclusion in the study if they were at clinical high risk of schizophrenia, aged between 13–35 years, had a total score of more than 20 on the Scale of Prodromal Symptoms (SOPS), and had an interest in participation in the clinical trial. Exclusion criteria included a history of suprathreshold psychosis symptoms (ie, no longer qualifying as prodromal) or clinical judgment that the reported symptoms from the SOPS were accounted for better by another disorder (eg, depression). Randomisation was done using a generated list with block sizes of four. Participants were stratified by site, with participants, investigators, and assessors all masked through use of identical looking placebos and centralised drug dispensation to study assignment. D-serine (60 mg/kg) was given orally in divided daily doses for 16 weeks. The primary endpoint was for negative SOPS, measured weekly for the first 6 weeks, then every 2 weeks. Participants who received at least one post-baseline assessment were included in analysis. Serum cytokine concentrations were collected at baseline, midpoint, and endpoint to assess the mechanism of action. Safety outcomes including laboratory assessments were obtained for all individuals. This trial is registered with ClinicalTrials.gov, number NCT0082620.
We enrolled participants between April 2, 2009, and July 23, 2012. 44 participants were randomly assigned to receive either D-serine (n=20) or placebo (n=24); 35 had assessable data (15 D-serine, 20 placebo). D-serine induced a 35·7% (SD 17·8) improvement in negative symptoms, which was significant compared with placebo (mean final SOPS negative score 7·6 [SEM 1·4] for D-serine group vs 11·3 [1·2] for placebo group; d=0·68, p=0·03). Five participants who received D-serine and nine participants who received placebo discontinued the study early because of withdrawn consent or loss to follow-up (n=8), conversion to psychosis (n=2), laboratory-confirmed adverse events (n=2), or protocol deviations (n=2).
This study supports use of NMDAR-based interventions, such as D-serine, for treatment of prodromal symptoms of schizophrenia. On the basis of observed effect sizes, future studies with sample sizes of about 40 per treatment group would be needed for confirmation of beneficial effects on symptoms and NMDAR-related inflammatory changes. Long-term studies are needed to assess effects on psychosis conversion in individuals at clinical high risk of schizophrenia.
“Of these components, aspirin (mean weighted effect size [ES]: 0.3, n = 270, 95% CI: 0.06-0.537, I(2) = 0), estrogens (ES: 0.51, n =262, 95% CI: 0.043-0.972, I(2) = 69%), and N-acetylcysteine [NAC] (ES: 0.45, n = 140, 95% CI: 0.112-0.779) showed significant effects. Celecoxib, minocycline [a, b, review and meta-analysis], davunetide, and fatty acids showed no significant effect. Conclusion: The results of aspirin addition to antipsychotic treatment seem promising, as does the addition of NAC and estrogens. These 3 agents are all very broadly active substances, and it has to be investigated if the beneficial effects on symptom severity are indeed mediated by their anti-inflammatory aspects.”
One review concluded that “the benefits with NSAID augmentation are, perhaps, too small to be clinically meaningful”
“Moderate to high quality evidence suggests small to medium benefits of adjunctive non-steroidal anti-inflammatory medications for reducing symptoms of schizophrenia.”
Adjunctive treatment with lisdexamfetamine dimesylate  or modafinil  is promising for improving negative symptoms but in some cases, may worsen positive symptoms. A systematic review and meta-analysis of randomized controlled trials for modafinil or armodafinil augmentation of antipsychotics found some small-sized benefits, concluding that augmentation with these agents: “reduces negative symptoms with a small effect size; the absolute advantage is also small, and the advantage disappears when chronically ill patients or those with high negative symptom burden are treated. Ar/mod does not benefit or worsen other symptom dimensions in schizophrenia.”
Compounds such as amphetamine or modafinil may exert their reward-related effects on behavior in part via a dopamine D1 receptor mechanism: D1 receptor agonists may have beneficial effects.
“High quality evidence suggests a medium effect of adjunctive donepezil or galantamine for improving overall and negative symptoms compared to placebo.
High to moderate quality evidence from pre-post comparisons of memory, attention and motor function showed some improvement following administration of adjunctive cholinesterase inhibitors (single- and dual-action); however, there was no significant benefit of adjunctive cholinesterase inhibitors compared to placebo for improving motor function, language or executive function. Evidence suggested possible benefit of cholinesterase inhibitors compared to placebo for improving visual learning and memory and visual attention (trail making task).
High quality evidence suggests single-action cholinesterase inhibitors alone (donepezil) may confer some benefit for attention and short-term memory.”
– Oxytocin has a role in the treatment of social/emotional deficits . While current research is still unveiling its effect on social domains, initial research is promising. Likewise, intranasal desmopressin is a promising adjunctive treatment for negative symptoms.
– 5-HT₃ antagonist augmentation is associated with significant reduction in negative symptom (SMD = 1.10), general psychopathology (SMD = 0.70), and total symptom (SMD = 1.03) ratings without reduction in positive symptom ratings. 
– Famotidine: “In the 1990s, the effect of an H2R antagonist, commonly used in the treatment of peptic ulcer, was evaluated in patients with SCH. During 3 weeks, in an open-label trial, ten patients received 20 mg twice a day of famotidine without interrupting their treatment with conventional antipsychotics. Famotidine led to significant reduction in the scores of Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impression (CGI), suggesting its administration as a useful alternative for SCH treatment. Later, another open-label trial was performed with 18 patients receiving 100 mg of famotidine daily, during 3 weeks. Significant improvements were found after measurements with BPRS, CGI, and the Schedule for the Assessment of Negative Symptoms (SANS). Recently, a randomized clinical trial for famotidine was performed with 30 patients with SCH, 16 patients received 100 mg of famotidine twice daily and 14 received placebo. Famotidine caused no significant adverse effects, and it led to great reduction in symptoms for both the Positive and Negative Syndrome Scale and CGI”.
– Augmentation with naltrexone (50mg bid) has demonstrated efficacy in treating some symptoms  A later study (doses of 200mg/day) failed to find any clinical benefit 
– Testosterone augmentation may be a potential therapeutic strategy in patients with schizophrenia 
– Allopurinol has rapidly resolved psychotic symptoms in some patients 
– Methylene blue, which blocks NO-dependent soluble guanylate cyclase-mediated intracellular signalling, has been shown to exert therapeutic effects as an adjuvant to established antipsychotics in the treatment for schizophrenia. Caution is required due to potent MAO-A inhibition by methylene blue with cases of serotonin syndrome being reported after combination with other serotonergic agents. 
– Tocilizumab, a IL-6 receptor antibody, is undergoing clinical trials  IL-6 has broad relevance in psychiatric illness, including an intriguing modulatory action on 5-HT2a receptors 
– Cyproheptadine, a first-generation antihistamine with additional anticholinergic and antiserotonergic properties is available over-the-counter in Australia and may augment some antipsychotics: “According to a small study, cyproheptadine hydrochloride has been found to improve sleep, calmness, as well as mood and energy levels, and to improve both negative and (sometimes even) positive psychotic symptoms in a subgroup of chronic schizophrenics who do not respond (either completely or sufficiently) to other therapies.
In clinical trials in which cyproheptadine was used as an adjunct to antipsychotic treatment for patients with schizophrenia, an improvement in negative symptoms was seen.” 
– 7,8-dihydroxyflavone shows promise  It is considered to be orally active, BBB permeable, metabolised into active O-methylated metabolites and produces sustained activation and internalisation of TrkB receptors with an affinity of ~10nM . Unfortunately, it has a relatively short half-life (~9 min with 1 mg/kg oral administration in rats). 4′-dimethylamino-7,8-dihydroxyflavone has improved properties that may make it better suited as a drug candidate.
– Enhanced GABAB signalling, preferably by positive allosteric modulation, improves PPI deficits in animal models  Anecdotally (from a single case study), acute administration of either baclofen or phenibut resulted in a reduction in the intensity of auditory hallucinations in a patient with clozapine resistant schizophrenia and further studies are warranted.
“Harte and O’Connor (2005) demonstrate that a reduction in the mPFC GABAB receptor-mediated inhibitory tone is associated with a disinhibition of PFC-mediated corticofugal glutamate drive onto both mesolimbic dopamine and GABA-containing neurons in the VTA while local intra-mPFC perfusion with the selective GABAB receptor agonist baclofen reverses this effect. Baclofen has been clinically tested as a possible antipsychotic and while it alone is not beneficial it has been proposed that cortical GABAB receptor activation may be a useful treatment in schizophrenia when co-administered with conventional neuroleptics” 
– Clonidine, potentially along with other α2-noradrenergic agonists, is capable of significantly increasing sensorimotor gating and normalising levels of P50 gating, which has a potentially high clinical relevance for the medical treatment of schizophrenia. 
– Potentially highly relevant to the treatment of negative symptoms, researchers found that “PCP-induced social withdrawal results from deficient endocannabinoid transmission and FAAH inhibition with URB597 reversed these deficits.” 
– Maprotiline produced the greatest reduction in alogia symptoms with a 50% decrease in severity 
– Addition of fluvoxamine to antipsychotics improves verbal memory. It is postulated that the mechanism involves enhanced GABA-A receptor/BDNF-dependent synaptic plasticity in the hippocampus 
-Addition of atorvastatin to risperidone was effective in reducing negative sign in schizophrenia although further studies seem to be needed