By: Erin Macpherson

Schizophrenia Treatment and Management
The primary treatment for schizophrenia is the use of anti-psychotic drugs 1 . However, anti-psychotic drugs target mainly the positive symptoms associated with the disease, (and not the negative or cognitive symptoms), and are associated with many side-effects. Further research is revealing the neural correlates of schizophrenic behaviour, allowing the development of new drug treatments. Treatment has expanded to also include cognitive behavioural therapy, social skills rehabilitation and family education programs.Treatment research is also seeking to reduce the duration of untreated psychosis (DUP) by identifying prodromal risk factors, identifying symptoms early, and responding with prompt drug treatment 2. Concerns in the management of schizophrenia include continued aggressive behaviour, depression and/or suicidal thoughts, relapses, and difficulty with reintegration to family and social situations 1.

7.1 Medication


Typical and atypical Antipsychotics

Typical, conventional, or first-generation antipsychotics block Dopamine D2 receptorsthroughout the brain, and were the traditional treatment for schizophrenia since their discovery in the 1950s, until the 1990s. Blockade of the mesolimbic dopamine pathway reduces the positive symptoms of schizophrenia, but can also block some reward pathways, leading to anhedonia, apathy, lack of interest in social interactions, and lack of motivation 3.The D2 receptors in the mesocortical dopamine pathways are also blocked, further reducing dopaminergic activity in this area, leading to increased cognitive and negative symptoms 3. These conventional antipsychotics can also lead to extrapyramidal symptoms (EPS) by reducing dopamine in the nigrostriatal pathway. Anticholinergic agents are often given concurrently with antipsychotics to reduce these EPS 3 . Five percent of patients on typical antipsychotics each year will also develop tardive dyskinesia , characterized by abnormal facial, tongue, and limb movements, which is potentially irreversible 3. However, if the patient has been on these medications for over fifteen years without developing these symptoms, it is unlikely that they will manifest in the future 3. These antipsychotics can also increase plasma prolactin, leading to weight gain, sexual dysfunction, and possible infertility 4. Some typical antipsychotics such as haloperidol, thioridazine, or chlorpromazine are still prescribed, however since their development in the 1990s, atypical antipsychotics are now typically the first choice for treatment 3.
Atypical antipsychotics also block dopamine receptors, but can dissociate rapidly from the D2 receptor, allowing improvement of positive symptoms without causing EPS. Recent research suggests that continuous D2 receptor occupancy is not necessary for effective treatment, but that occupancy of 60-70% is maximally effective 5. This is opposed to the 90% occupancy that occurs with typical antipsychotics 3. Some atypical antipsychotics couple a serotonin-2A antagonist with a D2 antagonist. The serotonin antagonist disinhibits dopamine neurons, causing dopamine release in certain brain areas. This decreases the risk for EPS, and for negative symptoms. Common atypical antipsychotics such as risperidone, paliperidone, olanzapine, quetiapine, ziprasidone, and clozapine are of this serotonin dopamine antagonist (SDA) class 3. Dopamine partial agonists (DPAs) are another class of atypical antipsychotics which create a balance between agonism and antagonism at the D2 receptor, stabilizing dopamine levels. These include amisulpride, and bifeprunox 3.
antipsychotic.jpg

Issues in antipsychotic medication treatment

The antipsychotic prescribed will depend on many individual needs and risk factors, and will attempt to achieve a balance between symptom reduction and harmful side-effects 3. Antipsychotics do reduce mortality of patients over the long-term, although certain antipsychotics have been implicated in better outcomes 6. Risperidone, quetiapine, olanzapine, ziprasidone, and aripiprazole are the atypical antipsychotics which are usually prescribed first; clozapine and typical antipsychotics can be used if the patient is unresponsive to these agents 3. Clozapine reduces suicide risk the most, and has the lowest discontinuation rate 6, but also has the most side-effects of all atypical antipsychotics 3, so is prescribed with caution. Continual and regular antipsychotic dosage is essential for its efficacy- intermittent drug therapy is not effective 1. Anti-psychotics taken every other day however, rather than every day, do not lead to an increase in schizophrenic symptoms or relapse. There was no change in drug side-effects however. Current practice emphasizes strict daily drug dosage in maintenance treatment of schizophrenia, but this recent research suggests that medication every other day can achieve the level of D2 receptor occupancy required for effective treatment 5. Psychiatrists can switch the type of antipsychotic medication prescribed based on individual’s responses, but care should be taken as symptoms such as thought disorder and hostility-suspiciousness tend to be vulnerable to changes in drug dosages or timing 1.
Atypical antipsychotics are associated with cardiometabolic side-effects including weight gain, diabetes, and cardiovascular disease 4.The introduction of these second-generation anti-psychotics was responsible for more cardiovascular related deaths 6. The sedative properties of antipsychotics are another concern, as this can lead to cognitive impairments. However, if the patient is violent or aggressive, sedation may be desired, and a benzodiazepine can be used in conjunction with the antipsychotic 3. Antipsychotics lead to decreases in global tissue volume, increases in CSF volume, and increases in both tissue volume and cerebral blood flow in the putamen. These changes are related to both the dosage and duration of antipsychotics. The global brain matter changes were found not to be a result of decreased number of neurons, but due to a decrease in astrocytes, a decrease in dendritic arborisation, and dendritic spine density. As a result, antipsychotics should be prescribed at the lowest effective dose 7.

Treatment of Cognitive and Negative Symptoms

Negative symptoms include anhedonia, apathy, disorganization, and social isolation. Cognitive impairments include declines in executive functioning, memory, and problem-solving, related to changes in the pre-frontal cortex and hippocampus 8. The severity of cognitive symptoms is the best predictor of future patient functioning, and everyday social and occupational success, so it is important that these symptoms of schizophrenia are treated in conjunction with treatment of positive symptoms 3. Serotonin receptor 1A agonism can improve cognitive and negative symptoms, as well as decreasing glutamate release, which can reduce positive symptoms as well 3. Oral glycine administration concurrently with antipsychotics has been found to reduce negative and cognitive symptoms by 34%, while not affecting the efficacy of the antipsychotics 9. The improvement persisted even after the glycine therapy was discontinued 9. D-serine is also implicated as an important compound in the hypofunctioning NMDA pathway which can be supplemented in schizophrenia treatment 10. Inhibition of the glycine transporter-1 (GlyT1) in astrocytes using sarcosine (N-methyl glycine) derivatives is also being investigated, although this method has been associated with side-effects such as ataxia, and decreased respiration, in animal studies 8. These inhibit the removal of glycine from the synapse to glial cells, increasing its activity at NMDA receptors 3. Abnormal GABA signalling is also thought to contribute to cognitive symptoms, especially working memory deficits, and tests to increase GABA transmission at several receptor sites have seen increases in cognitive function in mice 8. mGluR5 selective activators were found to increase working memory and learning abilities by increasing the activity of ionotropic receptors in order to counteract reduced NMDA receptor function 8. In animal models, the administration of AVE1625, a cannaboid CB1 receptor antagonist, improved working and episodic memory and reduced side-effects of typical antipsychotics while not reducing their efficacy 11. This provides potential for development of a similar drug in humans. Transcranial magnetic stimulation (TMS) has also been used to treat symptoms in some patients 1. Mood Stabilizers and antidepressants are often prescribed to combat emotional symptoms and changes to mood. Antidepressants can also help improve cognitive symptoms 3. Nicotine produces improvement with some negative and cognitive symptoms, including eye movement, and other movement problems; this may explain why schizophrenic patients have a higher smoking rate than the general population 8.

7.2 Psychosocial treatments




An individual diagnosed with schizophrenia will typically be seen by a case manager, who will refer the patient to several specialists who can assess physical, psychological and emotional health. Cognitive Behavioural Therapy (CBT) can help with positive symptoms not entirely controlled by antipsychotics by providing training to decrease the intensity of delusions and hallucinations 12. CBT has also been shown to improve some negative symptoms, to improve medication compliance, and to improve attitudes towards treatment 12. Long-term family and community therapies decrease frequency of hospitalizations and of relapses 12. Schizophrenic individuals with families trained to express emotion less experience fewer relapses 12. Social support programs are especially valuable for patients without a large support system of family and friends 12.
Employment programs are beneficial as the disease typically presents in young adulthood, usually before individuals have an established career. The best employment intervention programs provide work placements as soon as possible after treatment, and have regular follow-up with the individual 12.
Social skills training also proves beneficial. The level of community involvement, positive interpersonal behaviour, and employment success are used as measures of success of psychosocial interventions 13 .
Information about support programs for families of those with schizophrenia:
Information about the First Episode LEARN (Learning Employment Advocacy Recreation Network)


7.3 Relapse, Prognosis and Long-term Management




Antipsychotics generally improve positive symptoms within the first few weeks of beginning treatment 3.Residual phases can occur following an active psychotic phase, with the continuance of cognitive and negative symptoms. These symptoms lead to impaired everyday functioning, including difficulties with work, relationships, and sexual activity 7. These negative and cognitive symptoms remain stable for the year following an active episode 7. How severe symptoms are when the patient is released from hospital predicts the severity of symptoms one year later 7. It is essential following release from hospital that schizophrenia patients continue their medication; discontinuing administration within the first year results in a 25-30% increase in relapse risk 6. The side effects associated with antipsychotics are a major factor discouraging continuation of long-term treatment 3. Poor insight into the nature of their illness can also lead to noncompliance in drug treatments in an out-patient setting. This is highly correlated with relapses and hospital admissions 6. This highlights the importance of patient and family education, and continued follow-up care.
The first active phase of schizophrenia typically manifests in young adulthood, and episodes continue through the 20's and 30's 3. Patients are typically discharged from the hospital after each active stage is over. There are often several relapses, but the number of relapses experienced is specific to the individual 3. The neural mechanisms of relapse have not been fully investigated, but tissue loss and reduced brain volume from earlier psychoses are believed to play a role 15. With each relapse, the psychotic episode typically lasts for a longer period of time 3 and the residual symptoms generally worsen following each new episode 1. This leads to a deteriorated base functioning after each episode 3.
When the patient enters their forties, the disease typically becomes more stable, but the presence of negative and cognitive symptoms remains prominent. Patients tend to become more resistant to antipsychotics with continued use, especially in the later stages of the disease. Functional disability increases with the overall length of illness 13. In 2006, schizophrenic patients were expected to live an average of 22.5 years less than the general population 6. This is compared to a 25 year difference in life expectancy in 1996, just ten years earlier
6.
After an active phase, schizophrenic patients may have difficulty readjusting to life at home, and may struggle in social interactions. Sleep-wake cycles, personal grooming, concentration, and confidence can be affected 1. Depression and aggression are common, although violence towards others is not 1. Suicide is a major concern for schizophrenic patients, as in other psychotic disorders; 40% of schizophrenia patient deaths are due to unnatural causes, including suicide 16. However, the use of anti-psychotic medication reduces this risk of suicide 16.To measure success of treatment programs, many methods can be used. These include family reports, social skills performance assessment, specific level of functioning (SLOF) scales, the Personal and Social Performance (PSP) scale, the Positive and Negative Syndrome Scale (PANSS), and the Global Assessment Scale (GAS) 13. Treatment has transitioned from targeting chronic psychotic symptoms after they appear, towards identifying risk factors and initiated treatment during the prodrome, the period before psychosis 2. The goal is to reduce the duration of untreated psychosis (DUP). This can include antipsychotic treatment during the prodromal period 2. The Hillside Recognition and Prevention (RAP) Program explored the possibility of identifying prodomal symptoms- such as odd behaviours, suspiciousness, and social and academic difficulties- in adolescents at high-risk for mental disorders. Antidepressants, in conjunction with mood stabilizers, were actually found to be more beneficial than anti-psychotics at this stage of mental illness 2.
References

  1. Paterson, J., Butterill, D., Tindall, C., Clodman, D., Collins, A. Schizophrenia: an Information guide. Centre for Addiction and Mental Health (2009) http://www.camh.net/About_Addiction_Mental_Health/Mental_Health_Information/Schizophrenia/index.html
  2. Cornblatt, B, Lencz, T., Obuchowski, M. The schizophrenia prodrome: treatment and high-risk perspectives. Schizophrenia Research (2002) 54, 1-2, 177-186.
  3. Stahl, SM. Stahl’s Essential Psychopharmacology, Third Edition (2009) Cambridge University Press: New York.
  4. Ucok A, Gaebel, W. Side-effects of atypical antipsychotics: a brief overview. World Psychiatry. (2008); 7(1): 58-62.
  5. Remington, G., Seeman, P., Feingold, A., Mann, S., Shammi, C., Kapur, S. "Extended" antipsychotic dosing in the maintenance treatment of schizophrenia: a double-blind, placebo-controlled trial. Journal of Clinical Psychology. (2011) 72(8): 1042-8.
  6. Tiihonen, J, Lönnqvist J, Wahlbeck K, Klaukka, T, Niskanen L, Tanskanen, A, Haukka, J. 11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study).Lancet (2009); 374 (9690): 620–627.
  7. Ho, Beng-Choon, Andreasen, N.C., Ziebell, S., Pierson, R., Magnotta, Z. Long-term Antipsychotic Treatment and Brain Volume: A Longitudinal Study of First-Episode Schizophrenia. Archives of General Psychiatry (2011); 68(2):128-137.
  8. Coyle, JT, Balu, D, Benneryworth, M, Basu, A, Roseman, A. Beyond the dopamine receptor: novel therapeutic targets for treating schizophrenia. Dialogues in Clinical Neuroscience (2010); 12(3): 359-382.
  9. Javitt, D.C., Silipo, G., Cienfuegos, A., Shelley, AM, Bark, N, Park, M, Lindenmeyer, JP, Suckow, R, Sukin, SR. Adjuntive high-dose glycine in the treatment of schizophrenia. International Journal of Neuropsychopharmacology (2001); 4 (4):385-91.
  10. Labrie, V., Wong, A., Roder, J. Contributions of the D-serine pathway to schizophrenia. Neuropharmacology. (2012); 62(3):1484-1503.
11. Black, M et al. Roles of the Akt/GSK-3 and Wnt Signaling Pathways in Schizophrenia and AntiPsychotic Drug Action. Psychopharmacolgy (2011); 215: 149-163.
  1. Bustillo, J, Lauriello, J, Horan, W, Keith, S. The Psychosocial Treatment of Schizophrenia: An Update. American Journal of Psychiatry (2001); 158:163-175.
  2. Bowie CR, Leung WW, Reichenburg A, McClure MM, Patterson TL, Heaton RK, Harvey, PD. Predicting Schizophrenia Patients’ Real-World Behaviour with Specific Neuropsychological and Functional Capacity Measures. Biological Psychiatry (2011); 63(5):505-511.
  3. Gupta, S., Andreasen, N.C., Arndt, S., Flaum, M., Hubbard, W.C., Ziebell, S. The Iowa Longitudinal Study of Recent Onset Pschosis: one-year follow up of first episode patients. Schizophrenia Research. (1997); 23(1):1-13.
  4. Rizos, ., Papadopoulou, A., Laskos, E., Michalopoulou, P., Kastania, A., Vasilopoulus, D., Katsafouros, K., Lykouras, L. Reduced serum BDNF levels in patients with chronic schizophrenic disorder in relapse, who were treated with typical or atypical antipsychotics. World Journal of Biological Psychiatry (2010) (11) 2_2: 251:255.
  5. De Hert, M., Correll, C.U., Cohen, D. Do antipsychotic medications reduce or increase mortality in schizophrenia? A critical appraisal of the FIN-11 study. Schizophrenia Research. (2010); 117 (1): 68-74.