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International Journal of

Molecular Sciences

A Novel Bio-Psychosocial-Behavioral Treatment
Model in Schizophrenia
Yong-Ku Kim 1 , Joonho Choi 2 and Seon-Cheol Park 3, *
1 Department of Psychiatry, Korea University College of Medicine, Seoul 02841, Korea;
2 Department of Psychiatry, Hanyang University Guri Hospital, Guri 11923, Korea;
3 Department of Psychiatry, Inje University College of Medicine and Haeundae Paik Hospital,
Busan 48108, Korea
* Correspondence:; Tel.: +82-51-797-3300; Fax: +82-51-797-0298

Academic Editor: Johannes Haybaeck
Received: 28 February 2017; Accepted: 26 March 2017; Published: 30 March 2017

Abstract: Despite the substantial burden of illness in schizophrenia, there has been a discrepancy
between the beneficial effects of an increased use of antipsychotic medications and achieving
limited recovery or remission. Because the focus of the most common antipsychotic medications
is on dopamine, which is associated with positive symptoms, there is an unmet need for patients
with negative symptoms. Since cognitive and negative symptoms rather than positive symptoms
are more closely associated with psychosocial impairments in patients with schizophrenia, the
non-dopaminergic systems including glutamate and γ-aminobutyric acid (GABA) of the prefrontal
cortex should be of concern as well. The balance of excitation and inhibition has been associated
with epigenetic modifications and thus can be analyzed in terms of a neurodevelopmental and
neural circuitry perspective. Hence, a novel bio-psychosocial-behavioral model for the treatment of
schizophrenia is needed to account for the non-dopaminergic systems involved in schizophrenia,
rather than dopaminergic mechanisms. This model can be understood from the viewpoint of
neurodevelopment and neural circuitry and should include the staging care, personalized care,
preventive care, reducing the cognitive deficits, and reducing stigma. Thomas R. Insel proposed this
as a goal for schizophrenia treatment to be achieved by 2030.

Keywords: schizophrenia; bio-psychosocial-behavioral; model; neurodevelopment; neural
circuitry; cognitive

1. Introduction
Schizophrenia afflicts 0.5–1% of the world’s population and is clinically characterized by impaired
social and occupational functioning associated with misattributions or delusions, hallucinations,
cognitive deficits, thought disorder, negative symptoms, mood changes, and movement disorder. Most
patients with schizophrenia begin to present paranoid delusions and auditory hallucinations in late
adolescence or in early adulthood [1,2]. In the global burden of mental disorders, schizophrenia is
ranked third following unipolar depressive disorders and alcohol-use disorders with 14.4 million
disability-adjusted life years (DALYs) by the Grand Challenges in Global Mental Health Initiative [3].
Thus, the supply of effective and better treatments should be improved, and more effective and
affordable community-based care and rehabilitation techniques should be provided in order to reduce
costs and burden of severe mental illnesses including schizophrenia [4,5].
Despite this being a “golden age of psychopharmacology” [6,7], there is a discrepancy between
the beneficial effects of psychotropic medications and the lack of improvement for people with
schizophrenia [6,7]. Despite the revolutionary advances in genomics and neuroscience in the realm
of clinical psychiatry, the diagnostic methods for schizophrenia remain relatively unchanged [8–10].

Int. J. Mol. Sci. 2017, 18, 734; doi:10.3390/ijms18040734

bitopertin). the next-generation treatment model for schizophrenia has been proposed to overcome the problems and obstacles in the realm of clinical psychiatry that marked the period between 1980 and 2000 [6]. being far more complex and multi-causal than the dopamine overdrive theory suggests [18. a decrease in thalamic presynaptic dopamine D2 receptors. glycine transporter inhibitors (e.19].26–28]. and the inability to fully apply the emerging picture of schizophrenia neurobiology has been the common theme of schizophrenia treatment for the past two decades. and new use of current treatments. frontal cortex. and developing new interventions based on a personalized approach to the diverse needs and circumstances of patients with mental disorders [15]. Thus. metabotropic M2 /M3 agonists (e. clinical targets should be changed from symptoms to biomarkers or endophenotypes and clinical treatments should be more sophisticated and individualized. a combination of categorical and dimensional representations of psychopathology has been proposed to present the symptoms of affective psychosis and non-affective psychosis [12]. Additionally. 5th edition (DSM-5). However. and other factors are the obstacles for detecting the novel therapeutic targets for schizophrenia [25]. the heavy reliance on dopamine D2 antagonists. schizophrenia has been regarded as a “dopamine disorder” and the research has tended to seek a “pharmacological magic bullet” [18. the negative symptoms and cognitive deficits rather than positive symptoms are a major reason for the social and occupational dysfunctions in patients with schizophrenia and are not effectively treated with current antipsychotic medications [16. translating scientific advances into public health impacts is essential in terms of defining the pathogenesis of disorders from genes to behaviors. and substantia nigra and an increase in the proportion of D2D2 dimers and D1D2 dimers in the striatum.1.17]. antibiotics . Mol. the arbitrary diagnosis of schizophrenia with little biological validity. the aim of our paper is to present the necessity of a novel bio-psychosocial-behavioral treatment model in accordance with new molecular targets. Treatments for Negative and Cognitive Symptoms To treat negative symptoms. an increase in endogenous dopamine release. which can include cognitive deficits [16.19]. Interestingly.. in terms of accelerating the integration of psychiatry with the rest of medicine.g. and how to intervene to preempt disability. current antipsychotic medications are more effective for treating positive symptoms than treating negative symptoms. 734 2 of 11 Diagnosing schizophrenia not by the underlying biological underpinnings but by consensus on symptoms may be associated with significant heterogeneity in the clinical course and diversity in treatment responses to antipsychotics [6]. the focus of therapeutic interventions in schizophrenia has been preventing dopamine overdrive [20–24]. mapping the trajectory of illness to determine when. where. Sci.11]. Thus. dopamine overdrive in schizophrenia has been modeled as a dopamine supersensitivity psychotic reaction. not the diagnostic criteria for schizophrenia in Diagnostic and Statistical Manual of Mental Disorders.14]. the etiology of schizophrenia is actually more complex than these models would allow. pomeglumetad methionil). 2. 18. Hence. In terms of deconstructing the Kraepelinian dualism of psychoses. increased dopamine D2high receptors in the hippocampus. the failure to critically examine alleged “major advances”. the dependence on serendipity. Hence. 2. 2017. J. Thus. It has been modeled as a process of an excessive pruning of presynaptic neurons in the thalamus.Int. Hence. nicotinic and muscarinic cholinergic agents. a combination of categorical and dimensional representations is partly reflected by the Clinician-Rated Dimensions of Psychosis Symptom Severity [13. a lack of actionable biomarkers. from a disease caused by a chemical imbalance to one caused by dysfunctional circuitry [6. In a similar vein. the discipline of so-called clinical neuroscience has become a more important theoretical background for psychiatry than traditional models of psychosis [8–10]..g. new clinical targets. few acceptable animal models. Unmet Needs in the Current Antipsychotic Medications for Schizophrenia Although detecting disease-specific medications indicated for diverse symptom domains are ideal for antipsychotic treatments. Moreover. This would be in accordance with our improving understanding of schizophrenia. Instead. Hence.

has no clinical implications for treating negative and cognitive symptoms [16. . phophodiesterase (PDE) inhibitors and kynurenine aminotransferase (KAT II) inhibitors have been regarded as the novel approaches for cognitive dysfunctions. and targeting glutamate receptors have been evaluated as novel targets. behavioral and social dysfunctions of the disease.41]. lurasidone. oxytocin.38]. 2. 18. J. promising therapeutic agents include glycinergic agents (e. 5-HT2C agonists and 5-HT6 antagonists have been proposed as clinically useful agents for the early or prodromal stage of schizophrenia. Fifth. cannabinoid 1 (CB1) receptor antagonists and neurokinin 3 (NK3) receptor antagonists have been proposed as the potential antipsychotic strategies [42–44]. Sci. a glutathione (GSH) deficit has been associated with alterations in prepulse inhibition. anti-inflammatory agents have been evaluated in treating the early stage of schizophrenia [45. 2. agents with AMPA receptor activity have inconclusive therapeutic benefit [29. metabotropic 2 and 3 (mGlu2/3) receptor agonists which attenuate excessive glutamate release have clinical implications and are promising as well. acetylcholine. Sixth. since the relationship between elevated levels of kynurenic acid and declines in cognitive function in schizophrenia have been presented. In a model of interlocking nodes with a central hub. anti-oxidants have been evaluated for their ability to enhance neuroprotection and as an adjunctive strategy.. Multiple Interlocking Models Integrating Dopaminergic and Non-Dopaminergic Mechanisms In the pathogenesis of schizophrenia. negative and cognitive symptoms [37]. First. reactivity to stress.g. glutamate. the results were inconclusive [29–36]. serine and cycloserine) and glycine transport inhibitors. However.39]. GABA receptor function. which indirectly stimulate the NMDA receptor. However.. Recently. inflammation and oxidative stress have been proposed as the promising therapeutic targets for schizophrenia [25].37.40.48]. selective GABAA agonists and GABAB antagonists and allosteric modulators at GABAA receptor subtypes (α1. Second. because of a possible relationship between inflammation and schizophrenia. minocycline). N-acetyl cysteine increases the levels of GSH and has accordingly been suggested as another potential strategy for treating schizophrenia in a recent systematic review [47]. imbalance in any of these nodes can affect the entire system [25.2.46]. In addition. the results of these tests have so far proven inconclusive as well [16. representing oxidative balance and the immune system as inputs to the glutamatergic system.g. In addition. in terms of neuropeptides.. a broad range of genetic. since PDE contributes to degradation of the intracellular signaling pathways including cyclic AMP and cyclic GMP which have been associated with functions of dopamine and other neurotransmitters. and 5-HT3 antagonists have been evaluated as adjunctive treatments for negative and cognitive symptoms.g. the estrogen receptor modulator raloxifene and pregnenolone). glycine transport inhibitors. Unfortunately. agents targeting 5-HT1A activity have been evaluated for the treatment of negative and cognitive symptoms with better tolerability. whereas agents with D2/5-HT2A antagonism and/or 5-HT2A partial agonism are currently used. However. environmental risk factors and their interactions can alter many distinct neurotransmitter circuits. α7 nicotinic and M1 muscarinic agonists and allosteric modulators. glycinergic agents. cholecystokinin (CCK) receptor agonists. Targeting Non-Dopaminergic Mechanisms Non-dopaminergic mechanisms including serotonin. Additionally. Lastly. leading to the characteristic cognitive. Third. γ amino-butyric acid (GABA). Fourth.27–29. KAT II inhibitors have been proposed as another strategy to treating cognitive symptoms [38]. Mol. in terms of GABA receptor allosteric modulators. 2017. Seventh. hormones (e. NMDA receptor function. which has a potent 5-HT7 antagonism. dopamine transmission and neural synchrony in a mouse model of schizophrenia [25].Int.3. 3 and 5) are also promising therapeutic agents for schizophrenia [25]. in terms of glutamate transmission. 2. in terms of targets of serotonin. 734 3 of 11 (e. PDE inhibitors have been proposed as potential therapeutic strategies for treating positive.

. The decreased dopamine signaling via the reduced expression levels of markers of dopamine axons. the reduced expressions of PVALB mRNA have been presented in patients with schizophrenia [58. alterations in the DLPFC in patients with schizophrenia have been associated with reduced excitatory inputs to the DLPFC deep layer 3 pyramidal neurons. these findings suggest the following network model of schizophrenia: hypofunction of NMDA receptors located on PVALB-containing interneurons. 2017. The neurodevelopmental model has proposed that abnormality in the normal synaptic pruning and disturbances in the mechanisms of adolescence-related synaptic elimination contribute to excessive synaptic pruning and decreased spine number in patients with schizophrenia. Thus. Since postmortem studies for patients with schizophrenia revealed reduced levels of mRNA encoding the 67-kDa isoform of glutamic acid decarboxylase (GAD67 ) [57].62].51]. Sci. the dorsolateral prefrontal cortex (DLPFC) and primary auditory cortex are associated with cognitive and negative symptoms. inputs from dopamine neurons in the ventral mesencephalon can modulate the activities of pyramidal neurons and GABAergic interneurons. reduced levels of mRNA encoding GAD67 in the DLPFC interneurons may be a primary component of disease process and might contribute to pre-and post-synaptic changes including the reduced expressions of PVALB and GAT1 and elevated expression of GABAA receptor α2 subunits in patients with schizophrenia [61. Overall. J. impaired working memory) and negative symptoms (e. Mol. The alterations in the DLPFC have been implicated with several components for pyramidal neurons comprising about 75% of cortical neurons and utilizing glutamate.g.59]. reduced capacity to recognize spoken emotional tone) of schizophrenia are part of the disease process of schizophrenia.1. respectively. interneurons comprising about 25% of cortical neurons and utilizing GABA and axons from neurons in the thalamus and from dopamine-containing neurons in mesencephalon innervating targets in the DLPFC [19]. Alterations in the Circuitry of Dorsolateral Prefrontal Cortex Impairment in the working memory of patients with schizophrenia has been consistently characterized by disturbances in the manipulation of stored information and the maintenance of goal representations. reduced levels of glutamate-mediated excitation to midbrain dopamine and reduced availability of extracellular dopamine in the DLPLC may be associated with working memory impairments in patients with schizophrenia [63–66]. which coincide with alterations in the DLPFC circuitry [50. Findings from the postmortem studies for patients with schizophrenia have been inconclusive [54–56]. However. Thus. Interestingly. reduced expression of GAD67 .49]. decreased GABA production. such as tyrosine hydroxylase. disinhibition of pyramidal neurons and excess levels of glutamate at non-NMDA receptors [67]. 18. Schizophrenia from the Viewpoint of a Neural Circuitry The cognitive deficits (e. In terms of the defects in pyramidal neurons. since those with schizophrenia have presented the increased DLPFC activation with tasks requiring low levels of working memory and decreased DLPFC activation with tasks requiring high levels of working memory [52]. Reduced levels of GABA transporter 1 (GAT1) reportedly are found in the axon terminals of the chandelier neurons in PVALB-containing interneurons among patients with schizophrenia [60].g. The altered patterns in the DLPFC circuitry for patients with schizophrenia cannot be simply explained. . 3. whether there are alterations in mRNA or protein levels of NMDA receptor subunits in the DLPFC remains unknown. 734 4 of 11 3. in schizophrenia [19. Despite the unchanged number of calcium-binding protein parvalbumin (PVALB) neurons. decreased levels of GABA have been proposed as an improper neurotransmission pattern in the DLPFC.Int. mediated by the actions of AMPA and NMDA receptors on dendritic spines of pyramidal neurons [53]. and dopamine transporter..

Novel Therapeutics from the Viewpoint of a Neural Circuitry Hence. genes. 734 5 of 11 3. hypoxia and starvation) and clinical features of offspring with schizophrenia (disturbances in executive function. 18. since they regulate spine size. Alterations in the Visual Circuitry It is known that the morphological and functional anomalies in almost the entire visual tract.2. when combined with a relevant .73]. Hence.3.. Eye tracking dysfunction (ETD) has been proposed as an endophenotype associated with genetic and environmental factors from the neurodevelopmental perspective in schizophrenia. Thus. Thus. Prenatal infection and enlargement of the cavum septum pellucidum/diminished intracranial volume is also linked to schizophrenia [83].Int. occur in schizophrenia. The influences of mild isolation stress during adolescence in rodents on behavioral profiles and DNA methylation of the gene encoding tyrosine hydroxylase in mesocortical dopaminergic neurons. Alterations in the Circuitry of Auditory Cortex Reduced gray matter volume and an accelerated loss rate of gray matter in Heschl’s gyrus have been observed in patients with schizophrenia. J. from the retina to the cortex. retinoic acid). Herein. 2017.71]. working memory and verbal memory and structural brain abnormalities) are observed in large birth cohort studies with clinical. 3. neurotrophic factors (e. 4.75]. the visual circuitry has been proposed as a research tool for biological mechanisms of information processing deficits in schizophrenia [70. It has been suggested that the defects in proteins. an electroencephalogram (EEG) wave known as the mismatch negativity (MMN) is related to the magnitude of progressive reductions in gray matter of Hesch’s gyrus in the early stage of schizophrenia [68].4. the visual anomalies in schizophrenia might contribute to alterations in the visual circuitry associated with neurodevelopmental defects during the embryonic period. Moreover. such as the projection from the hippocampus to the DLPFC. it has been expected that the new types of therapeutic targets beyond manipulating neurotransmitter systems would be identified and validated with analyzing the pathological neural circuits in the etiology and pathogenesis of schizophrenia. are being formed [74. Interesting. infection). environment (e. neurocognitive and neuroimaging measures [76–82]. Reconceptualizing Schizophrenia from a Neurodevelopmental Perspective Maternal stress during the first trimester of pregnancy is associated with elevated risk of schizophrenia in male offspring. Sci. 3. One potentially promising therapeutic target are spine-specific kinases. the specific vulnerability to perturbation of the retinoic acid receptors rather than other brain areas has been considered to be significantly involved in defects from the neurodevelopmental perspective of schizophrenia. retinoic acid has been regarded as a candidate for regulation of the retinal development. number and functions [72. and/or a combination of these factors. environmental and epigenetic factors has been suggested in the etiology and pathogenesis of schizophrenia. events during prenatal and early life may influence the development of schizophrenia. genome and epigenome [84]. alcohol. Mol. and neurotrophic expressions during the first four weeks of the embryonic period may be associated with ETD-related anatomical and functional abnormalities. Moreover. In conclusion. Associations between in utero exposures to prenatal risk factors (infections. It has been suggested the existence of allele-specific epigenetic differences in genes associated with psychosis constitute a further element in the dynamic interplay between the environment.g. since it plays a significant role in the early stages of embryonic development.g. The MMN in patients with schizophrenia can be mimicked by infusion of NMDA receptor antagonists into the auditory cortex of animals [69]. It has been proposed that these anomalies are due to defects in the neurodevelopmental processes involving genes. stress is particularly harmful if presented during the phase of development when neural circuits.. an integrative model of genetic.

Focused on cognitive and/or negative symptoms. Stage II is characterized by the features of cognitive. reducing the cognitive deficits. 5. Insel [84] has defined the stages of schizophrenia as follows: Stage I is characterized by genetic vulnerability and environmental exposure. Hence. J. Schizophrenia has been neurodevelopmentally modeled as follows: reduced elaboration of inhibitory pathways and excessive pruning of excitatory pathways in children that develop schizophrenia leads to alterations in the excitatory-inhibitory balance in the prefrontal cortex and reduced myelination. which have been proposed as a vision for schizophrenia in 2030 [2. rather than measurement-based care is needed to understand and treat schizophrenia in terms of multi-dimensional natures in the DSM-5 [89]. particularly negative symptoms. there may be stages of schizophrenia [84]. treatment with polysaturated fatty acids. In accordance with reconceptualizing schizophrenia in terms of the neurodevelopment and neural circuitry perspective. being intervened with medications and psychosocial interventions. help seeking. 734 6 of 11 genetic risk including a genetic variant of DISC-1 [85]. Using not only the clarification of subtle clinical features but also the advent of biomarkers and new cognitive tools. it has been suggested that the RDoC may reveal the developmental trajectory at neuroanatomical level and sensitive periods of developmental period. being diagnosed through cognitive assessment. the current treatment target is focused on the dopamine.91]. which is mainly associated with positive symptoms. Sci. 6. and little to no cognitive deficit. However. Targeting non-dopaminergic mechanisms including glutamate and GABA systems. behavior and symptom. and social support. The integration of epigenetic effects into bio-psychosocial-behavioral models of schizophrenia is expected to provide novel insights to the biological underpinnings of the onset and course of schizophrenia [84]. Mol. focusing on the imbalance of excitatory-inhibitory signals . possibility of being diagnosed with genetic sequence and family history. it has been suggested that the integration of neurodevelpmental models and approaches to the RDoC in the etiology and pathogenesis of schizophrenia may enlighten the novel targets for intervention and specifying the timing of intervention. psychosocial interventions and rehabilitation services. the loss of insight into one’s condition. Interventions are medication. Stage III is characterized by the features of abnormal thought and behavior and relapsing-remitting course. preventive approaches. The RDoC implies that targeted pharmacological treatment individualized to the patient. it may be possible to detect earlier stages of risk and prodrome [90]. circuit. This disorder in synaptic connectivity is directly responsible for the symptoms of schizophrenia. The Research Domain Criteria (RDoC) is constituted by a dimensional rather than a categorical system and easily enables to link different levels of molecule. 2017. personalized care. Identifying what the prodromal neurodevelopmental changes are will undoubtedly enable preventive intervention [2]. it has been suggested that the reconceptualizing schizophrenia can be consistent with a novel bio-psychosocial-behavioral model dealing with complexity of the recognition and treatment [86]. neuroimaging and the Structured Interview for Prodromal Syndrome (SIPS). Lastly.Int. Conclusions In terms of the etiology and pathogenesis of schizophrenia.88]. Interventions at this stage could include cognitive training. unemployment and homelessness. behavioral and social deterioration. Moreover. can cause a schizophrenia-like phenotype. medical complications and incarceration. integration of care and reducing stigma. cognitive and negative symptoms rather than positive symptoms have been more closely associated with functional recovery or remission in patients with schizophrenia. stage IV is marked by continued deterioration. 18. defining a novel bio-psychosocial-behavioral treatment model for schizophrenia is needed to be consistent with staging care. The marked heterogeneity between patients with schizophrenia can be studied effectively with the RDoC rather than traditional diagnostic barriers [87. A Novel Bio-Psychosocial-Behavioral Treatment Model in Schizophrenia From the viewpoint of neurodevelopment. as revealed through clinical interview. From a neurodevelopmental perspective.

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