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Data on prevalence and costs associated with the disease

Schizophrenia affects more than 23 million people worldwide, being the major psychological disorder, with devastating personal, family and social impact⁽¹⁾. Due to the significant chronic disability, total costs associated with the care and treatment of these patients is impressive, although progress has been made towards intervention, and the psychopharmacological type has gained momentum especially since the development of atypical antipsychotics. In 2014, the annual global cost of schizophrenia in German society ranged between 9.63 and 13.52 billion euros⁽²⁾. Between 2005 and 2008, costs associated with US schizophrenic care were $74.74 billion indirect costs and $17.1 billion direct costs. Direct medical costs include those related to hospitalization, outpatient checkups, emergency room consultations, private consultations, home visits for medical assistance and prescriptions. Indirect costs are represented by the loss of productivity associated with low activity levels, productivity loss associated with labor, premature mortality/suicide, and costs associated with care (cost of support workers)⁽³⁾. It can be seen that the lack of functional recovery, through maintaining caretaker dependence and the lack of socio-professional reintegration, is the most important cause of disease-generated costs. However, the administration of an optimum treatment can reduce by up to 22% of the overall cost associated with this major mental disorder⁽⁴⁾. It is now widely accepted that negative and cognitive symptoms affect 40% and 80%, respectively, of people suffering from schizophrenia. In addition, both symptomatic dimensions have significant weight and a majority in determining the unfavorable functional prognosis even in patients achieving an adequate remission of positive symptoms⁽⁵⁾.

Another important aspect is the life expectancy of patients with schizophrenia, which has several factors that contribute to its reduction. In this regard, one can enumerate increased frequency of unhealthy behaviors (excessive smoking, alcohol and other psychoactive substances, sedentary lifestyle etc.), naturally increased frequency of chronic medical comorbidities (common genetic susceptibility between schizophrenia and type 2 diabetes, schizophrenia and obesity etc.), and the occurrence of chronic medical comorbidities secondary to the administration of antipsychotic medication (metabolic syndrome induced by some atypical antipsychotics). Somewhat paradoxically, although the profile of tolerance and safety with the occurrence of antipsychotic medication is considered to have improved compared to conventional antipsychotics, a study conducted in England between 1999 and 2006, based on national health records, showed that the standardized mortality rate in patients with schizophrenia increased relatively steadily from 1.6 (95% CI; 1.5-1.8) in 1999 to 2.2 (95% CI; 2.0-2.4) in 2006 (p<0.001 in reference to frequency)⁽⁶⁾. If we accept this assertion as true, that the safety profile and tolerability of atypical antipsychotics have improved compared with conventional antipsychotics, then it might be possible that a lack of improvement in unhealthy behaviors combined with a relatively low adherence to treatment of patients with schizophrenia constitute a significant part of the causality of this phenomenon. Nontherapeutic adherence and persistence of unhealthy behaviors should rather be attributed to the cognitive dimensions of schizophrenic symptomatology as an intrinsic part of what persists between acute episodes. Or unfortunately, current medication effectiveness for symptoms of this type remains quite modest⁽⁷⁾.

Neurobiological support of cognitive and negative symptoms in schizophrenia

The existence of cognitive symptoms requires the presence of a neurobiological support which in the case of schizophrenia precedes the onset of psychosis. The first to conceptualize the cognitive component of schizophrenia was the German psychiatrist Emil Kraepelin, who named this psychosis “Dementia praecox”, believing that once onset begins, it will invariably lead to the deterioration of psychic functions. Structural neuroimaging studies and modern brain mapping have highlighted that indeed with the progression of the disease and just before onset a thinning of certain regions occurs in the brain’s cortical layer. Thompson et al. observed that in patients with schizophrenia with onset as early as adolescence existed a certain dynamic thinning of the cerebral cortex. Around the age of 13 years old, the thinning of cortical layer was significant compared with healthy subjects and targeted especially the parietal lobe, which has a role in supporting oculo-spatial function and associative thinking. Five years after the first mapping, the extensive damage has extended to the cortical layer and the anterior pole to the brain, temporal lobes, comprising the sensorimotor cortex, dorsolateral prefrontal cortex and orbitofrontal zones. These patterns were correlated with the severity of psychotic symptoms and reflected neuromuscular, auditory, visual and frontal executive function disorders present in the clinical picture of schizophrenia. In temporal regions, gray matter loss was completely absent at disease onset, but it was later generalized. The last cerebral modifications included the dorsolateral prefrontal cortex and superior temporal gyrus regions with deficits consistently highlighted in previous studies conducted on populations of adult patients⁽⁸⁾.

Genetic markers of cognitive and negative symptoms in schizophrenia

Another direction of research is aimed to highlight the genetic and epigenetic molecular mechanisms, which could form the basis for the emergence of cognitive and negative symptoms of schizophrenia, being an area of great interest for the scientific community. An extensive review of literature highlighted the following candidate genes associated with increased risk for schizophrenia: genes that intervene in the dopaminergic neurotransmission – for example, gene associated with the synthesis of COMT (allele wave), responsible for the decrease in dopamine in the prefrontal cortex; followed by genes involved in the synthesis of proteins involved in the neurodevelopment process, such as the associated gene with DISC1 (disrupted in schizophrenia 1, which synthesizes a protein involved in the processes of neurogenesis, neuronal migration and dendritic organization, transport of synaptic vesicles at the level of presynaptic glutamatergic neurons that control the intracellular signaling cAMP that affect glutamatergic neurotransmission), or the gene responsible for the synthesis of BDNF (brain-derived neurotrophic factor); genes responsible for encoding the synthesis of the molecules/receptors that intervene in serotonergic neurotransmission (e.g., the gene responsible for the synthesis of HTR_2A serotonin receptor subtype). At the end of this review, the authors stress that glutamatergic neurotransmission associated genes (whose dysfunction is considered to best explain the cognitive symptoms of schizophrenia) represent only 6% of the studies found in databases that they reviewed. This underlines the need to identify a new psychotropic class that can further target glutamatergic dysfunction, in order to improve the cognitive dimension of the clinical picture of schizophrenia⁽⁹⁾. According to Stahl (2013), the NMDA receptor-mediated hypofunction at the level of the prefrontal GABA interneuron (containing parvalbumin) is the basis for: cognitive symptoms (decrease of dopamine in the dorsolateral prefrontal cortex) – attention deficit, executive dysfunction, memory impairment, vocal fluctuations etc.; negative symptoms (decrease of dopamine in the dorsolateral prefrontal cortex and the ventromedial prefrontal cortex) – blunted affect, alogia, avolition, anhedonia, lack of social networking etc.; affective symptoms (reduced dopamine in the ventromedial prefrontal cortex) – depression, suicidal ideation etc⁽¹⁰⁾.

The association between cognitive and negative symptoms with neuroimaging markers

Structural neuroimaging studies have shown interest in cortico-striato-thalamo-cortical circuits that have involvement with regions such as the prefrontal cortex, hippocampus, entorhinal cortex, anterior cingulate gyrus etc. In patients with schizophrenia, there are: neurodevelopmental anomalies consisting in a reduction of the white matter mass (in particular the uncinate and arcuate fasciculi) and a decrease in intracranial volume; neurodegeneration anomalies with a reduction of gray matter mass (neuronal bodies and neuropil) and the decrease of global brain volume and pro-inflammatory mechanisms⁽¹¹⁾. Other studies reported changes in the total cerebral volume relative to the clinical progression of schizophrenia (Figure 1)^(12,13). It can be seen that there is a decrease in total cerebral volume in patients with unfavorable clinical evolution. Following these studies, it is difficult to establish the temporal relationship between cerebral volumetric changes and the form of clinical evolution of the disease, given that at the time of neuroimaging investigations the diagnosis of schizophrenia was already established in the studied subjects.
 

A superior stage of imaging research is that of functional neuroimagistics, which is not limited to volumetric changes but also shows the functional change in certain brain regions, dependent upon the execution of a particular task in patients with schizophrenia compared with healthy subjects. Kanahara et al. compared regional cerebral blood flow (rCBF) using computerized tomography and single photon emission (SPECT) in two groups with schizophrenia (a group of 33 patients and a group of 40 patients with schizophrenia without deficit syndrome). The group with deficit syndrome presented a significant decrease in rCBF in the right orbitofrontal prefrontal cortex (OFC) and in the right anterior insular cortex, compared to the non-deficit group. These results demonstrated that hypofrontality in remission was a common feature among the groups and suggested that the OFC could play an important role in the development of negative symptoms in people with severe deficit syndrome⁽¹⁴⁾. According to some research, the anterior portion of the insular cortex is activated during emotions generated by maternal attachment, as well as those associated with reward⁽¹⁵⁾. The orbitofrontal portion of the prefrontal lobe integrates information from the temporal association cortex, amygdala and hypothalamus, together making the superior center for integration of emotional processing, having an important role in social cognition⁽¹⁶⁾. Finally, these changes could explain the neuroanatomic and neurofunctional substrate of schizophrenia’s negative symptoms.

Association between negative and cognitive symptoms with markers of neuroinflammation

The presence of deficit syndrome and negative symptoms was studied and correlated with the presence of inflammation markers, such as tumor necrosis factor alpha (TNF-) and interleukin 6 (IL-6). In one study, both markers were associated with the presence of deficit syndrome and following multiple regression analysis, TNF- was highlighted as predictive for the appearance of affectivity, alogia, and total score for negative symptoms⁽¹⁷⁾. Other studies have associated the presence of IL-6 with the presence of cognitive symptoms in schizophrenia⁽¹⁸⁾.

Neurodevelopmental aspects of cognitive and negative symptoms

From the neurodevelopmental perspective, there is a generally accepted view that negative symptoms and cognitive symptoms long precede positive symptoms, possibly even pre-puberty. This period is attributed to an intense activity of cerebral restructuring, constituted of consolidation of certain synapses and the removal of other unnecessary ones. Also, during this period, mainly in the prefrontal cortex, there is a significant reduction in excitatory glutamatergic synapses, an increase in turn of the number of GABA-ergic inhibitory synapses and also of the dopaminergic type. Anomalies in this period of intense neuroplastic activity could be responsible for the aforementioned symptoms. This newer neurodevelopmental paradigm does not contradict but rather is complementary to that of aberrant neural migration in the second trimester of fetal life. Given the non-disruptive character of these symptoms, they attract attention quite late, with the moment of their apparition being reconstructed retrospectively after the onset of the first episode of psychosis. The presence of negative and cognitive symptoms is the largest impact of the degree of schizophrenic disability, with the tendency to persist beyond the remission of positive symptoms to which they are independent (Figure 2). Moreover, the therapeutic response in the case of their cognitive and negative symptoms remains modest with respect to the currently available medication^(19-22).
 

Standardized assessment of negative and cognitive symptoms in schizophrenia

Together with the data obtained during the anamnesis and heteroanamnesis, it is necessary to standardize and evaluate the recorded present symptoms. This is done with both the techniques and instruments offered by qualitative psychopathology (e.g., operational diagnostic criteria, structured diagnostic interviews etc.), but especially by quantitative psychopathology or psychometry (e.g., psychopathological assessment scales). In the following, we will briefly review only the most commonly used assessment scales of cognitive and negative symptoms. We will keep in mind the battery of cognitive tests approved through the project of the NIMH-MATRICS workshop in the United States of America.

Standardized assessment of negative symptomatology

The most commonly used scales are: Scale for the Assessment of Negative Symptoms (SANS), Positive and Negative Syndrome Scale (PANSS), Negative Symptom Assessment, and others^(23-26). There are also a number of other psychopathological rating scales for schizophrenia, which during factorial analysis revealed items with acceptable confidence and validity to quantify negative symptoms.

Standardized assessment of cognitive symptoms

A working group has been developed in the USA with the acronym MATRICS (Measurement and Treatment Research to the Improve Cognition in Schizophrenia) endorsed and sponsored by the National Institute of Mental Health (NIMH). The purpose of this group is to improve cognition in schizophrenia through increasing research quality in the intrinsic cognitive domain of this disease. MATRICS identified seven cognitive domains that are fundamentally affected in schizophrenia, which have been included in the test battery MCCB (the MATRICS Consensus Cognitive Battery): 1. Learning and verbal memory; 2. Learning and visual memory; 3. Working memory; 4. Attention and vigilance; 5. Processing speed; 6. Social cognition; 7. Reasoning and problem solving. The MATRICS Working Group has made the decision that schizophrenia research should focus on these areas, to identify neurobiological mechanisms in order to develop new pharmacological treatment strategies⁽²⁷⁾. Although with a discriminative capacity and a reduced confidence level, it has been identified on the basis of the factorial analysis and a cognitive sub scale of PANSS, which includes the items P2 – Conceptual disorganization, N5 – Abstract thinking, G10 – Disorientation and G11 – Problems of attention⁽²⁸⁾. In order to assess cognitive function, the Wechsler Adult Intelligence Scale can be utilized fully or in part with certain subscales.

Clinical and psychometric evidence of the emergence of cognitive symptoms produced in schizophrenia

As already mentioned, the emergence of cognitive symptoms precedes the onset of the first psychotic episode. In this respect, the most significant studies are population cohort studies (cohort covering populations at risk of illness or the entire population in a given geographical area, born within a delimited time) and those studies that include patients from onset who did not benefit from any antipsychotic treatment. Drawn-out evolution and the presence of antipsychotic treatment could be considered confounding factors for assessing the cognitive status of patients with schizophrenia, these two interfering with the accuracy of the data⁽²⁹⁾.

A meta-analysis that included 13 prospective studies on birth cohort or increased genetic risk and retrospective studies on population groups indicated that low IQ evaluated at 13 years of age presented an odds ratio (OR) of 0.51 (95% CI; 0.38-0.65), which constitutes an important factor in the prediction of the onset of schizophrenia. IQ assessment at a more advanced age did not have the same effect on prediction⁽³⁰⁾. Another meta-analysis, which included four adolescent and youth population cohorts (n=10,717), revealed that verbal ability at 18 years of age did not have predictive capacity for schizophrenia or schizoaffective disorder: OR=0.78 (95% CI; 0.60-1.01; p=0.06). Instead, the verbal ability level between 13 and 18 years old had predictive ability for schizophrenia or schizoaffective disorder: OR=0.88 (95% CI; 0.42-0.79; p<0 .001)⁽³¹⁾.

The results from 4^th, 8^th and 11^th grade students on the Iowa Test of Basic Skills and Iowa Tests of Educational Development were obtained for 70 subjects who later developed schizophrenia. The average percentile range of the subjects’ scores in vocabulary, reading, language, math, sources of information and composite categories were compared to the state norms. Subjects obtained under the 50^th percentile for each category in all three classes, but only scores in language, reading, and sources of information were significantly lower for the 11^th grade students than state norms. Regarding longitudinal evolution, there was a significant linear decrease in language scores over time. Scores from the 11^th grade students were positively correlated with WAIS-R IQ, verbal fluency and Rey auditory verbal learning test scores at the first episode of illness. Grade 11 students’ scores were not significantly correlated with the age at onset of the disease or the evaluated disorganization, psychotic or negative symptoms. Academic scores for grades 4 and 8 were insignificant below average in this group of children who later developed schizophrenia. However, the test scores dropped significantly between grades 8 and 11. This corresponds to the period of 13-16 years of age, or the beginning of puberty. Poor or declining school performance may be a precursor to cognitive impairment during the first episode of illness (Figure 3)⁽³²⁾.
 

Another study aimed to examine neuropsychological functions in patients with schizophrenia who have never been exposed to neuroleptics and had their first episode (FE) psychosis. Subjects were consecutively recruited and included 37 patients with FE schizophrenia who had never been exposed to neuroleptics. These subjects were compared to 65 previously untreated but previously treated patients (PT) and 131 healthy control subjects. Patient groups had almost identical profiles, presenting generalized disorders, especially verbal memory and learning, vigilance, rapid visual-motor processing and attention. Memory and verbal learning represented the bulk of the variance between patients and control subjects, and the elimination of this effect substantially mitigated all the other differences. By contrast, both the FE and PT groups continued to show significant deficits in memory and verbal learning after attention, abstraction and all other functions were controlled. Some functions which are not commonly involved in schizophrenia (spatial cognition, fine motor speed and visual memory) were more affected in the PT group than in the FE group. Verbal memory, as a primary neuropsychological deficiency present at the beginning of schizophrenia, involves the left temporo-hippocampal system. Neuropsychological assessments before treatment allow for the differentiation between primary deficits and secondary deficits due to medication or chronic history. This is essential for developing a neurobehavioral perspective of schizophrenia⁽³³⁾.

Cognitive deficits persisting beyond remission of a psychotic episode have been confirmed by a study of 82 patients and 107 control subjects; suitable in terms of age and gender, were evaluated at baseline and at a 1 year follow-up. It can be observed that when evaluating after 1 year, cognitive deficits remained stable for the inhibition control domains (inhibition control is our ability to control evident behavior, such as impulses and motor reactions), WCST perseverative responses (flexible thinking and the ability to switch between different concepts or strategies that can be classified as our flexibility abilities) and the most pronounced for letter fluency (letter fluency involves associative exploration and retrieval of verbal information, such as phonetic and semantic material) – Figure 4⁽³⁴⁾.
 

A therapeutic aspect that is extremely important is the functional recovery of patients with schizophrenia, beyond clinical remission of symptoms during the acute phase of the disease. While the therapeutic activity may still be modest with the existing antipsychotics on cognitive symptoms, this could explain the relatively small percentage of patients reaching this ultimate therapeutic goal. A prospective study, over a period of nine months, included patients with a first episode of psychosis, during which they received specific treatment. A battery of neurocognitive tests were used, which included evaluation of working memory, attention, perceptual processing, verbal memory and processing speed, which were correlated to an assessment of occupational/educational reintegration through the use of the Strauss-Carpenter scale. The results of the study indicated that the battery of neurocognitive tests predicted 52% of the variance in terms of occupational/educational reinsertion at nine months, after the patient was clinically stabilized in the outpatient clinic⁽³⁵⁾. A survey on a sample of 117 people with schizophrenia and 77 healthy control participants highlighted that the domains of the MCCB battery of tests such as composite score, processing speed, vigilance and working memory were correlated with job performance, which were measured dichotomously: employed or unemployed⁽³⁶⁾.

Cognitive and negative symptoms in schizophrenia – clinical and therapeutic implications

In this section we will expose, in the form of tables, the main clinical and therapeutic recommendations available for situations where there is a predominance of cognitive and negative symptoms in the clinical picture of schizophrenia.

Predominance of cognitive symptoms

Predominance of negative symptoms

New psychopharmacological guidelines for the remission of cognitive and negative symptoms in schizophrenia

Research in psychopharmacology has identified neurotransmissions and new receptors as substrate for the action of a new class of antipsychotics, which may result in further improvement in the remission of cognitive and negative symptoms in schizophrenia. These are summarized in Table 3 (Gaebel, 2011).

Combined psychopharmacological and psychological approach to cognitive and negative symptoms in schizophrenia – therapeutic strategy with superior results

So far, in many studies, integrated treatment has proven its superiority to a simple approach consisting only of administering antipsychotics.

Certainly, the type of psychological intervention should be individualized and selected based on the symptomatological profile in the clinical picture. Thus, a meta-analysis, which included 48 comparative studies, has revealed that cognitive-behavioral therapy (CBT) was significantly more effective than the other combined interventions in reducing the positive symptoms. Social skills training were significantly more effective in reducing negative symptoms. CBT was significantly more effective when compared directly with the supportive counseling techniques for both symptoms in general, and positive symptoms specifically⁽⁴²⁾.

A basic intervention, psychoeducation, should begin as early as possible and include both the patient and their relatives. The basic objectives of psychoeducation are⁽⁴³⁾:

• Ensure the acquisition of “basic competence” of patients and their relatives.

• Facilitate informed and responsible disease management.

• Deepening the role of patients as an “expert”.

• “Co-therapists” – strengthening the role of relatives.

• The optimal combination of professional and empowerment therapies.

• Improving understanding of the disease and improving compliance.

• Promoting relapse prevention.

• Engaging in crisis management and suicide prevention.

• Supporting healthy components.

• Management of informational and educational activities.

Including psychoeducation, administrated on the short term, significantly reduced the number of days of hospitalization and the rate of rehospitalization in two years in the subgroup of patients who received this type of integrated treatment strategy, in comparison to those who received only medication⁽⁴³⁾.

Cognitive remediation techniques remain essential in achieving remission of cognitive symptoms in schizophrenia and implicitly in functional recovery. In this respect, a meta-analysis that included 26 randomized, controlled, cognitive rehabilitation studies in schizophrenia, totaling 1151 patients, revealed that cognitive remediation was associated with significant improvements in cognitive performance, symptoms and psychosocial functioning in schizophrenia. The effects of cognitive remediation on psychosocial functioning were significantly more pronounced in studies that provided adjuvant psychiatric rehabilitation than those that provided only offered cognitive remediation⁽⁴⁴⁾.

The effectiveness of cognitive remediation techniques has also been demonstrated by correlating them with functional neuroimaging techniques. A meta-analysis, aimed at selecting correlation studies between cognitive restructuring technique (CRT) and the activation of certain brain areas, selected 9 studies from 162 initially selected articles. ALE analyzes (meta-analysis of probability of activation probability), which compared pre- and post-training brain activation, showed increased activity in the lateral and medial prefrontal cortex, the parietal cortex, the insular cortex and caudate nucleus, and the thalamus. In particular, activation associated with CRT in the left prefrontal cortex and in the thalamus partially overlaps with previously identified meta-analytic areas associated with work memory deficits, executive control and emotional face processing in schizophrenia. We conclude that in this first set of studies, CRT interventions, carried out in various theoretical modalities, stimulate plasticity in brain regions that support cognitive and socio-emotional processes. Although preliminary, these changes appear to be both restorative and compensatory, even though the thalamic-cortical areas previously associated with cognitive dysfunction may be common sources of plasticity for cognitive remediation in schizophrenia⁽⁴⁵⁾.

There is a possibility of combining several psychotherapeutic techniques with pharmacological treatment. A randomized controlled trial included 1,280 patients in the early stage of schizophrenia, and had two research arms: one only with antipsychotic medication, and the other with additional psychological education, family intervention, skills training and cognitive-behavioral therapy. Applying the combination therapy resulted in⁽⁴⁶⁾:

Significant reduction in the risk of interruption for any reason and relapse (Figure 5).
 

Gaining significantly greater improvements in terms of discernment, social functioning, day-to-day activities and in four evaluated domains of quality of life (QoL).

Significantly improved probability of obtaining a job or access to education

Conclusions

Schizophrenia remains the most serious mental illness, not due to the epidemiological impact, but as a consequence of the significant degree of disability of the individual. This disability is exponentially consequential to the total associated cost of the disease. In addition to the measurable costs, there are also intangible costs, such as those related to the quality of life and well-being of both patients and relatives involved in their care.

Negative and cognitive symptoms of schizophrenia have its origins in the very early life of the patient, which interferes unequivocally with clinical outcome and especially the functional outcome of this mental illness. Early detection of these symptoms is unfortunately poorly realized and this should trigger an alert for professionals in the mental health community.

Neuroimaging studies have indicated that patients with schizophrenia with negative symptoms or deficit syndrome have an abnormal pattern of activation of different brain regions that are intertwined from a functional point of view. These complex neural networks represent the neurobiological support of higher psychic functions affected by cognitive and negative symptoms.

Evidence based on highly rigorous methodologies, the most valuable being meta-analysis in this regard, have shown that cognitive deficits, including those related to social cognition, have been present since childhood. This makes the performance, both academic and social, of individuals who subsequently develop schizophrenia to experience a decline from childhood to adolescence.

There is a great discrepancy between the progresses made in the field of neuroimaging and consequently of biological psychiatry and those of psychopharmacology, that fails to keep up to the former. Unfortunately, the effectiveness of antipsychotics on cognitive and negative symptoms of schizophrenia remains only modestly fulfilled to date. However, research continues in an effort to identify new mechanisms of action to make antipsychotics more effective on all symptomatic dimensions of schizophrenia.

Due to its complexity, with biopsychosocial origins, the approach in terms of treatment of schizophrenia cannot be limited to pharmacological treatment. Besides this, the interventions of psychosocial model have convincingly shown that it remains the only option in the therapeutic management of schizophrenic patients, which has resulted in improvements regarding cognitive and negative symptoms.

Finally, we believe that fast progress in the domains of genetics and epigenetics, neuroimaging, of biological psychiatry as a whole, along with diversified techniques of psychosocial intervention, reserves hope for patients with even the most severe clinical forms, of whose clinical picture is significantly burdened by cognitive and negative symptoms.