Negative Symptoms in Schizophrenia – A Review of Neurobiology, Diagnosis and Management

PREVALENCE OF NEGATIVE SYMPTOMS

Up to 60% of patients with schizophrenia have prominent or predominant negative symptoms that are clinically relevant and need treatment. [Correll C & Schooler N et al., 2020]

• In first-episode psychosis, negative symptoms are noted in 90% of patients, and 35-70% of patients continue to have clinically significant negative symptoms despite treatment.
• Amongst patients with negative symptoms, 73% had negative symptoms before the onset of positive symptoms, and 20% experienced them within the same month as positive symptoms. [Correll C & Schooler N et al., 2020]
• The CLAMORS study showed that in routine clinical practice, 61% of stable outpatients with schizophrenia who are receiving antipsychotic treatment were found to have at least one symptom of moderate severity or worse on the PANSS scale. The most common negative symptoms include social withdrawal (48%), emotional withdrawal (42%) and poor rapport (39%), were the most common symptoms. [Bobes J et al., 2010]
• In the CATIE Study of 1442 individuals with schizophrenia, prominent negative symptoms were common. They were present in 40% of patients, with 19% of outpatients having prominent negative symptoms without prominent positive symptoms, and 21% having both positive and negative symptoms. [Rabinowitz J et al., 2013]

HISTORY OF NEGATIVE SYMPTOMS

The original description of negative symptoms goes back to the time of Kraepelin and Bleuler.  Kraepelin coined the term “dementia praecox” and highlighted the features of indifference, emotional deficits and, in particular, the lack of volition.

He reported that the “ability to feel emotion” was intact, despite a lack of will to seek it out, reminiscent of anticipatory anhedonia.

Bleuler stated: [Bleuler, E. 1950]

They sit about the institutions to which they are confined with expressionless faces, hunched up, the image of indifference.

An indifference to everything – to friends and relations, to vocation or enjoyment, to duties that arise, to good fortune or bad.

The capacity for work, for caring, for themselves diminishes.

They no longer have the urge to do anything, either of their own initiative or at the bidding of another. They can spend years in bed.

Kraepelin in 1906 described blunting as a core feature of dementia praecox and stated:

failure of mental activities

loss of mastery over volition

Dede and Guiraud (1929) describe instinctual/intellectual weakening and athymhormia (loss of vital force).

Schneider described first-rank symptoms which had a significant focus on positive symptoms at the expense of negative symptoms.

The notion of negative symptoms could be attributed to the 19th Century English Neurologist, Reynolds, who in reference to epilepsy, distinguished symptoms like loss from gain, spasms and loss anaesthesia. [Messinger et al., 2011]

Carpenter conceptualised that it is important to differentiate primary negative symptoms inherent to the disease process from secondary negative symptoms, which may be a consequence of many environmental, medication and psychological factors. [Carpenter W et al., 1988]

Deficit Syndrome

Brian Kirkpatrick highlighted that a primary negative symptom type of schizophrenia might be termed as a deficit syndrome associated with an inferior outcome and can be found in 1/3 of patients with schizophrenia. [Kirkpatrick, B et al., 2001]

NEUROBIOLOGY OF NEGATIVE SYMPTOMS

The neurobiology of negative symptoms is distinct from that of positive symptoms. Positive symptoms are predominantly mediated by the mesolimbic pathways and involve the dopamine and glutamate networks.

Negative symptoms, on the other hand, involve fronto-cortical temporal and cortico-striatal pathways.

Of note, hypo-dopaminergic signalling in the prefrontal cortex is postulated as an underlying factor of negative symptoms. The disruption of the cortico-striatal loops is strongly implicated in deficits in anticipatory and consummatory pleasure.

3 main networks play a part in motivation and reward.

• (DLPFC – dorsal striatum): Goal-directed activity and planning for reward acquisition

• Orbito Frontal cortex to ventral striatum: Value of reward, prediction, timing, and delayed discounting (value vs delay).

• Anterior cingulate cortex to ventral striatum: Cost of obtaining a reward, monitoring effort invested, and competition.

Dysfunction in these circuits underlies the anhedonia and amotivation components of negative symptoms.

 In a nutshell, patients with schizophrenia are unable to assemble, get motivated by and explore/export/exploit information about previous pleasurable experiences in the service of goal-directed and effort-requiring attainment of future reward.[Millan M et al., 2014]

Structural Aspects

A decrease in grey matter volume of the temporal lobe, particularly the superior temporal gyrus (linked to the theory of mind), has been associated with negative symptoms. [Millan M et al., 2014]

The temporal lobes are strongly connected to the frontal lobes, which comprises the fronto-cortico-temporal pathway. Negative symptoms are associated with reduced connectivity in the following networks.

• Prefrontal cortex and insular, occipital and temporal cortices.
• Prefrontal cortex and the striatum.
• Superior temporal gyrus to the fronto-cortical regions, like the anterior cingulate.
• Networks within Parietal cortex

Role of Dopamine (D3) Receptors: 

D3 receptors are situated in the mesolimbic regions of the brain and control reward, emotion and motivation.

D3 receptors possess a high affinity for DA (420-fold higher than that of D2 receptors) and, unlike D2 receptors, small changes in their number or function may lead to dramatic effects on synaptic transmission. Thus, D3 receptors  could be critical modulators of normal dopaminergic function and cognition. [Maramai et al, 2016].

D3 receptors are postulated to play a role in the modulation of negative symptoms, mood and cognition. [Correll C & Schooler N et al., 2020]

• Antagonism and partial agonism of dopamine D3 receptors can mediate social interaction improvements, anti-anhedonic and pro-cognitive effects.
• D3 antagonism in the midbrain can increase dopamine neurotransmission to the prefrontal cortex and the nucleus accumbens, reversing hypodopaminergic functioning linked to negative symptoms and mood deficits.
• The increase in dopamine in the prefrontal cortex could activate D1 receptors, which, in turn, could further mediate improvements in cognition and negative symptoms.
• D3 receptors are also known to increase acetylcholine in the prefrontal cortex and regulate glutamatergic excitability.

NMDA Hypofunction Hypothesis 

NMDA antagonism by ketamine and phencyclidine produces a condition similar to schizophrenia, with both positive and negative symptoms.

Hypoactivity of frontocortical NMDA receptors results in reduced GABAergic interneurons activity, leading in turn to the disorganisation of neural networks linking cortical and subcortical structures.

Abnormalities in NMDA receptor functions seem to interfere with brain plasticity (ability to form long-term synaptic connections), which may cause not only psychosis but also the negative symptoms and cognitive impairments of schizophrenia. [Tsapakis E et al., 2015]

Other receptor mechanisms mediating negative symptoms include the role of the metabotropic mGluR2 receptor and alpha-7 nicotinic receptor.

EEG Findings

1. A decrease in delta slow-wave sleep associated with negative symptom severity.
2. Increases in slower rhythms, including episodic memory-related frontal cortical hippocampal theta, is linked to the intensity of negative symptoms.

Social cognition impairments 

Social cognitions are the suite of mental operations used to monitor social signals from others and decipher their emotional status and intentions. Social cognition is important for social engagement, integration and maintenance of normal social relationships.

Temporal gyri are linked to social cognition, including facial and gaze processing.

Social cognition impairments may be linked to the dysconnectivity between the frontal lobe, prefrontal cortex and the temporal cortex, including the superior temporal gyrus.

The superior temporal gyrus, in particular, is linked to the “theory of mind”.

Every day, humans engage in a wide variety of social interactions to achieve a diverse set of social goals that include acquiring information, influencing a partner’s behavior through, and maintaining emotional intimacy through sharing thoughts and feelings. Integral to an individual’s success in these social encounters is his or her ability to reason about the thoughts, beliefs, and feelings of others to predict behavioral responses. This ability has been termed theory of mind. [Premack and Woodruff, 1978], [Baron-Cohen et al., 1985]

Oxytocin

Oxytocin, a pro-social neuropeptide plays an important role in social behaviour and motivation.

The disruption of an oxytocin-modulated network incorporating the superior temporal gyrus, inferior frontal gyrus, PFC and insula cortex, may contribute to social withdrawal in schizophrenia. [Millan M et al., 2014]

BURDEN AND COURSE OF NEGATIVE SYMPTOMS

So, we start off with genetic underpinning and other factors (trauma, in utero insults) and then carrying some negative symptoms already even into the first episode.  These are usually rather subtle and non-specific; often depressogenic symptoms (social withdrawal and apathy) and sometimes this is mixed up with illicit drug use, which confounds the picture and makes it difficult to tease apart. 

 Even within this early phase, negative symptoms tend to predict a poorer outcome. Then you can see the psychotic symptom bursts coming through in the late teens and early twenties.  You can also see that negative symptoms actually, to some degree, abate, with some restitution later in life.  (Prof Castle)

The prodromal onset of negative symptoms has been characterised as a risk factor for the switch to psychosis.

The long-term negative symptoms course is unclear, with some studies reporting a fluctuating course whilst others reporting relative stability over time.

Negative symptoms are present throughout the course of schizophrenia. They can occur early, persist over time, increase in severity, and remain between acute episodes of illness.

The burden of negative symptoms

• The negative symptoms are associated with worse functional outcomes, such as occupation and academic performance.
• It can also impact household integration, affecting social functioning, participation in activities and quality of life.
• Avolition that is associated with amotivation, asociality and anhedonia, is a key negative symptom that is associated with functional deterioration.
• Individuals with schizophrenia have anticipatory anhedonia, which may be linked to impairment in executive function that may constitute avolition, interfering with goal-directed behaviour to seek activities that provide a reward.
• Five variables have been associated with real-life functioning in patients with schizophrenia, of which negative symptom constructs are an important part. [Mucci et al., 2021]

1. Neurocognition associated with everyday life and work skills
2. Avolition with interpersonal relationships
3. Positive symptoms with work skills
4. Social cognition with work skills
5. Interpersonal functioning

CLINICAL EVALUATION OF NEGATIVE SYMPTOMS

Questions to evaluate negative symptoms

1. What level of mood are you in?
2. How do you feel today?
3. How do you spend a typical day?
4. What do you do for fun?
5. Have you had a chance to meet up with people outside your family recently?

I think, both with the patients and the families, it is important to explicitly talk about the negative symptoms and describe them as a part of the illness.  There is a lot of social stigma around psychotic illnesses and schizophrenia in particular, there is that self-stigma. 

So, understanding that these are a core part of the illness, that it is as much a symptom as the hallucinations. [Dr Dark]

Clinicians should also differentiate between primary (an intrinsic part of schizophrenia) and secondary negative symptoms (due to contributory factors) which can be challenging.

Negative symptoms can be detected using the Positive and Negative Syndrome Scale (PANSS), which is considered the gold standard in clinical trials [Tsapakis et al. 2015]:

• Positive and Negative Syndrome Scale (PANSS) – Developed in 1987, this complex scale of 7 items requires a structured approach and standardized training but has high validity and sensitivity.
• Scale for the Assessment of Negative Symptoms (SANS) – Is widely used to measure negative symptoms and has good validity and reliability due to its 20-item clinician-rated scale that can segregate negative symptoms from positive symptoms.
• Brief Psychiatric Rating Scale (BPRS) – Another widely used rating scale that can detect the presence of emotional withdrawal and affective flattening; however it has been shown to inadequately assess the full range of negative symptoms.
• Negative Symptoms Assessment (NSA-16) – A 16-item scale with good psychometric properties; however, it has poor clinical usefulness due to the length of time required to complete this assessment.
• Brief Negative Symptom Scale (BNSS) – This scale is designed for clinical trials and involves a 13-item instrument that has high retest reliability and consistency for both the global score and individual subscales.
• Clinical Assessment Interview for Negative Symptoms (CAINS) – This novel semi-structured, 7-point, 23-item instrument addresses experience- and expression-related deficits such as expression of emotion, motivation, and pleasure.
• Negative Symptoms Assessment 4 – NSA4 – The NSA4 has four verbatim items from the full rating scale (restricted speech quantity, reduced emotion, reduced social drive and reduced interest). It can be used successfully with clinical staff training.

MANAGEMENT OF NEGATIVE SYMPTOMS

Measurement based care is probably something which we don’t do very well when it comes to negative symptoms.  Are we really looking at improving negative symptoms?  Or are we really looking at functionality of the patient?  I think we need to do both. 

If you really look at functionality, we need to train ourselves and the family and caregivers as to how to identify the minimal improvements in the patients. [Prof Pai]

Pharmacological Treatments: 

Second-generation antipsychotic medications

Antipsychotic medication is a cornerstone of the treatment of positive symptoms of psychosis, improving symptoms in 81% of first-episode schizophrenia cases and 51% of patients with chronic schizophrenia.

However, there is insufficient evidence of their benefits in negative symptoms.  Some studies have shown improvements in negative symptoms; however, it is unclear whether this is due to the treatment of positive symptoms that contribute to negative symptoms or a primary direct benefit from the antipsychotic medication.

For example, The CATIE study showed no significant advantages in efficacy for any of the atypical antipsychotics with regard to negative symptoms.  [Lieberman J et al., 2005]

A recent review evaluated the role of Serotonin-dopamine activity modulators (SDAMs) and showed that aripiprazole, cariprazine, and brexpiprazole may reduce negative symptoms. [Brasso et al,,2023].

Lumateperone, a high-affinity 5-HT2A antagonist, a moderate affinity D2 and D3 partial agonist α1 and α2 antagonist, and low-affinity M1, M3, M4, and 5HT2C antagonist did not improve negative symptoms.

Aripiprazole also showed efficacy as an augmentation agent in the treatment of negative symptoms in treatment-resistant schizophrenia.

The authors concluded that according to the available evidence synthesised in the current review, among SDAMs and antipsychotics in general, only cariprazine may represent an effective strategy to reduce these disabling negative symptoms. [Brasso et al,,2023].

Amisulpride

• Amisulpride is a D2/D3 antagonist.
• The D3 pre-synaptic antagonism at lower doses is postulated to increase prefrontal dopamine, contributing to its action against negative symptoms. 5HT7 antagonism is also hypothesised in the improvement of negative symptoms with amisulpride.
• Other agents, such as olanzapine, also have 5HT7 antagonist; the additional receptor interactions at muscarinic receptors, histamine receptors, counteract the 5HT7 antagonist benefits.
• A meta-analysis of antipsychotic medications in negative symptoms of schizophrenia showed that amisulpride was the only antipsychotic that was superior to placebo in treating predominant negative symptoms.  However, a parallel reduction of depression makes it difficult to differentiate whether the improvements are due to negative symptoms or depression.  [Krause M, et al., 2018]

Cariprazine

• Cariprazine is a dopamine D3 and D2 receptor partial agonist with tenfold higher affinity for D3 receptors than for D2 receptors.
• Antagonism at D3 autoreceptors can enhance dopaminergic neurotransmission, especially in such brain areas as the prefrontal cortex, where dopamine release appears to be controlled by D₃
• Cariprazine has similar D2 affinity to aripiprazole but a higher D3 partial agonist-antagonist affinity at D3. The higher D3 preferring effects may exert pro-cognitive effects. [Citrome, L. 2015]
• A large 26 -week RCT comparing the effects of fixed-dose cariprazine; 3mg, 4.5mg or 6mg per day, and risperidone; 3mg, 4mg or 6mg per day, on predominant negative symptoms of patients with stable and limited positive symptoms and without relevant depression or EPSEs showed significant differences and clinically relevant improvement in both negative symptoms and functional impairments in favour of cariprazine over risperidone, suggesting a meaningful clinical benefit for cariprazine in negative symptoms. [Németh G et al., 2017]
• Superiority regarding negative symptom improvement with cariprazine was also accompanied by improvements on the Clinical Global Impression Improvement Scale and the Personal and Social Performance Scale, indicating the improvement of the negative symptoms with cariprazine led to clinically meaningful advantages.

α-2 Adrenoreceptor Blockers

• Antipsychotic medications with an α-2 adrenoreceptor blockade may have benefits in negative symptoms as the α-2 adrenergic blockade can increase frontocortical dopamine.
• At this point, there is no clear evidence for atypical antipsychotics with α-2 adrenoreceptor blockade in the treatment of negative symptoms.

Antidepressants

• A meta-analysis has shown that antidepressant augmentation may be potentially beneficial in treating negative symptoms of studies. [Galling B, et al., 2018]
• Mechanisms such as 5HT2C antagonism, which can increase PFC dopamine, may be involved.
• However, benefits are modest, and it is unclear whether NS are directly impacted or indirectly improved via the alleviation of depressed mood.

Psychostimulants

• Psychostimulants increase fronto-cortical dopamine, which theoretically could treat negative symptoms; however, the concurrent increase of dopamine in the mesolimbic pathways could worsen psychosis.
• Lisdexamfetamine, as an adjunct to antipsychotic therapy, showed improvements in NS. [Lasser A et al., 2013]
• Modafinil augmentation [Arbabi M et al., 2012] has shown benefit, but armodafinil did not. [Kane J et al., 2012]

Overall, there are arguments that strengthening compromised mesocortical dopamine transmission in schizophrenia might favourably influence negative symptoms, but rigorous proof is lacking.  No agent has yet been described that specifically recruits this mechanism to alleviate negative symptoms and this is unlikely to be sufficient alone. [Millan M et al., 2014]

Anxiolytics and positive modulation of GABA-A receptors

• There is some evidence that a reduction of social anxiety might secondarily diminish negative symptoms.
• The loss of the GABA-A α-2 subunit in the pyramidal neuron may contribute to the dysconnectivity of frontocortico – subcortical glutamatergic circuits.  Benzodiazepines or positive allosteric modulators (PAMS) of the GABA-A receptor may improve this dysconnectivity. [Millan M et al., 2014]
• Pregnanolone, for example, of which the metabolised allopregnanolone also acts as a PAM at GABA-A receptors, shows some evidence in negative symptoms. [Marx C et al. 2009], [Ritsner M et al., 2014]

Anticonvulsant augmentation

• Lamotrigine and topiramate augmentation has shown inconclusive results. [Tsapakis E et al., 2015]

Modulators of NMDA receptors

• Since NMDA receptor hypoactivity is associated with negative symptoms, Glycine and D-cycloserine, which are glycine receptor agonists, were thought to show promise in managing negative symptoms; however, no significant effect was identified.
• Similarly, biopterin, a highly selective antagonist at glycine 1 transporters, also failed to demonstrate an effect.
• However, the NMDA antagonist Memantine as an add-on therapy to risperidone showed a significant improvement in negative symptoms. [Rezaei F et al., 2013]

Minocycline

• Minocycline is a broad-spectrum tetracycline antibiotic trialled as an add-on therapy to target the inflammatory hypothesis of negative symptoms.
• It has shown some benefits as an augmentation strategy. [Tsapakis E et al., 2015]

N-acetylcysteine 

• Add on NAC at 2 g/day has shown benefit in negative symptoms but not for cognitive or positive symptoms. [Farokhnia M et al., 2013]

Omega-3 fatty acids 

• A meta-analysis revealed statistically significant but not meaningfully relevant results. [Joy C et al., 2006]

Oxytocin 

• Oxytocin may counter negative symptoms by promoting social motivation or via enhancement of theory of mind.
• Oxytocin interacts with various neuromodulators in the expression of its actions, including 5HT and dopamine, in the nucleus accumbens and amygdala.
• Data suggest intranasal oxytocin can normalize functional connectivity in an Amygdala-to-left-Middle temporal gyrus (MTG) /Superior Temporal Sulcus (STS) / Angular gyrus (AG) circuit that contributes to negative symptoms in SZ. [Abram S et al., 2020]

Others

Agents acting on:

• α-7 nicotinic receptors
• sigma-2 receptors
• 5-HT2A receptors

Roluperidone (MIN-101), an antagonist at both sigma-2 and 5-HT2A receptors without dopamine affinities, demonstrated efficacy in reducing negative symptoms vs placebo in stable patients with schizophrenia in Phase 2B trial. [Davidson M et al., 2017]

• A subsequent phase III trial did not reach significance, but a post hoc re-analysis of phase 2b showed that roluperidone can reduce emotional experience and emotional expression sub-scales. [Harvey et al. 2020]
• Roluperidone also reduced avolition in another network analysis examining key domains related to negative symptoms.
• Furthermore, a network analysis aimed at determining which domains were central to negative symptoms showed that avolition was a central symptom within this network of negative symptoms and that roluperidone effectively reduced its centrality. [Strauss et al. 2020]

NEUROSTIMULATION

Transcranial Magnetic Stimulation (TMS)

• High-frequency rTMS of the prefrontal cortex, particularly the dorsolateral prefrontal cortex, is reported to be effective in the relief of negative symptoms when applied for several weeks early in the course of schizophrenia, independent of any change in depressive symptoms. [Prikryl R et al., 2013]
• A 10 Hz setting at left DLPFC for or at least 3 consecutive weeks with a 110% motor threshold (MT) was the best rTMS parameter for treating negative symptoms. [Shi C et al., 2014]

Transcranial Direct Current stimulation (tDCS)

• A recent RCT showed that active tDCS was superior to sham in ameliorating negative symptoms, with superior response rates (20% improvement) for negative symptoms. [Valiengo D et al., 2020]

PSYCHOSOCIAL INTERVENTIONS IN SCHIZOPHRENIA

General behavioural interventions

• Healthy lifestyle – emphasis on exercise, sleep, diet, smoking cessation, moderate alcohol consumption, social participation

Social skills training

• Social skills training aims to moderate negative symptoms by using intensive and structured modules that educate patients about the skills needed to improve their social function in the community.
• Social skills training was used in the early intervention “Opus” program in Denmark, improving negative symptoms in first-episode psychosis. [Nordenoft M et al., 2015]  Social skills training was coupled with family psychoeducation.

4. Cognitive Remediation Therapy

• Cognitive remediation (CR) aims to endurably rekindle key skills related to neurocognition and social cognition. It has been shown to recruit a distributed network of fronto-cortical structures, including the inferior frontal gyrus, DLPFC and anterior cingulate cortex. [Wykes T et al., 2011]

• A network meta-analysis showed that CR could have small to moderate beneficial effects on negative symptoms. [Cella M et al., 2017]

5. CBT

• Addressing defeatist beliefs, negative expectations and asocial preferences.
• Cognitive behavioural therapy specifically targets poor motivation, anhedonia, and negative and defeatist beliefs and promotes patients’ active engagement to attain defined goals.
• It can be oriented to individual strength, and its core objective improves functional status and recovery.
• Several studies support the role of CBT in treating Negative symptoms and improving functional outcomes and quality of life. [Tsapakis E et al., 2015]

All of us know what it is like to have no motivation, so you can talk about things like, ‘I’m here today at work because that’s what I do, it’s a routine and just like me, you’re going to need a routine, in fact you’re going to need it more because what we understand about this illness is that you have less natural drive, your get up and go has got up and went before mine’.  So, you really normalise it and that can be so simple but such an effective intervention in CBT.

Making a little bit of fun but always retaining hope.  I might be able to talk a bit later about non-pharmacological intervention.  A person in my SCIT group with profound negative symptoms, 20 weeks of therapy and at the end we do a check-in and they said, “I’m feeling anxious” and I almost said, “Yes!!” because he could identify emotion.  Later we had a celebratory lunch after the group and he was smiling and interacting and initiating conversation. [Dark] 

6. Family Interventions

• Help family members and patients cope with symptom through psychoeducation, communication, behavioural problem solving and crisis management.
• Family psychoeducation adjunctive to standard care is effective at decreasing negative symptoms and thus reducing relapse and rehospitalisation.
• Family-based interventions help increase medication adherence, reduce symptoms, and improve functional and vocational status among patients. [Tsapakis E et al., 2015]

7. Motivation and Enhancement Training (MOVE)

MOVE is a home-based manual driven treatment consisting of 5 components:

1. Antecedent control
2. Anticipatory pleasure
3. Emotional processing and expression
4. CBT to address self-defeating thoughts
5. Skill building.

The results in negative symptoms are not conclusive. [Velligan D et al., 2015]

8. Yoga

• Yoga therapy aimed at improving social and occupational function was reported to increase plasma oxytocin levels. [Jayaram N et al., 2013]

It is a long-winded approach but there are a number of interventions.  Exercise has some benefit, music, metacognition interventions and making people more aware to help them enact some routine behaviour. 

There is a lot but they are going to be a small effect, so you have to do a good formulation on what will work for that individual and what your resources are to leverage that. 

Also, bring your team along with you because if we educate our staff to have an understanding that when they are doing exercise it is not just exercise we are targeting, we are targeting negative symptoms and we are targeting cognition.  Our staff need to be metacognitively aware of that themselves, to make sure that they understand the therapeutic benefit. 

Part of this isn’t just a medication, it isn’t just a new psychosocial intervention, it’s training up a modern workforce that understands schizophrenia beyond positive symptoms. [Dr Dark]

CONCLUSION

We still need to, obviously, treat positive symptoms; it is very difficult to do functional rehabilitation with ongoing severe positive symptoms but I would always say, the residual negative symptoms, don’t just be satisfied with them, make sure that you are assessing them, that you are treating any ones which might be secondary, including secondary to some of the medications which you might be using and treat other causes – depression and anxiety are really important – but also keep hope and keep on pushing the psychosocial.  [Prof Castle]

The negative symptoms of schizophrenia are characterised as deficits of behaviour that profoundly affect a patient’s quality of life.

Negative symptoms are also closely related to both cognitive and positive symptoms, forming a spectrum of inter-related deficits.

From a pharmacological perspective, Amisulpride and Cariprazine have shown promising evidence for negative symptoms.

rTMS and tDCS are possible neurostimulation techniques showing promise.

Psychosocial interventions should be considered key components in treating negative symptoms as they can help the patient and family cope with symptoms with clinically meaningful results.

Although there are many treatment modalities, the underlying concepts of disease and how to accurately measure clinical efficacy of newly developed drugs are not clearly defined.

As such, new therapeutics have moved beyond the traditional treatment models to further refine our understanding and management of negative symptoms.

RECOMMENDED BOOKS