In the first version of this CPG schizophrenia phases were divided into acute phase, stabilization phase and stable phase, and a special section was created for schizophrenia in childhood and adolescence. Additionally, a section on first episodes was introduced, which described new research lines in early phases of psychosis. Subsequently, this research has been widely developed and has promoted the implementation of numerous specific programs in different parts of the world: Australia and New Zealand, Canada, Great Britain, Nordic Countries, Holland, Germany and Spain. This has favoured the appearance of increasing scientific evidence of the potential benefits of early intervention in psychosis. Hence, the phase encompassing the period prior to the onset of the first psychotic episode and the first five years of evolution of the disorder is currently known as early phases of psychosis or incipient psychosis phase, and it has been determined that it can contribute to:²⁰⁶

1. Avoid biological, social and psychological impairment which, generally speaking, can occur in the years following the onset of the psychotic disorder.²⁰⁷
2. Decrease comorbidity.
3. Favor faster recovery.
4. Improve prognosis.
5. Help maintain psychosocial skills.
6. Maintain family and social support.
7. Decrease the need of inpatient care.

Given the importance of early intervention to avoid or minimize the development of the disorder, this section has been reorganized in the following structure:

7.1. Early phases of psychosis: 7.1.1. High risk mental state phase 7.1.2. First psychotic episode phase 7.1.3. Recovery phase and critical period 7.2. Schizophrenia phases: 7.2.1. Acute phase 7.2.2. Stabilization phase 7.2.3. Stable phase

7.1. Early phases of psychosis: incipient psychosis

The evolution of the disorder in these phases and the delay in treatment can lead to disturbance in life circumstances, such as academic and employment failure, self-aggression, changes in interpersonal relationships, interfamily conflicts, etc. These disturbances can produce what is known as “psychological toxicity”, the effects of which can limit the subsequent level of recovery from the disorder even if later, at the onset of the first psychotic episode, it is treated effectively.^208,209

Hence, intervention in this phase should be aimed at detecting the disorder as early as possible and applying the most appropriate treatment for each situation.

7.1.1. High risk mental state phase

This phase, also known as the phase with high risk of developing psychosis or the initial prodromal phase, is characterized by a disturbance in emotional, cognitive, behavioural or social functioning and by the presence of unspecific prodromes.

Previously, the concept of prodrome was used as a precursor and predictive factor of psychosis. Yung and collaborators posed a conceptual change, replacing the notion of prodrome with high risk mental state (HRMS).²¹⁰ In this perspective, the initial prodrome of psychosis shifts from being seen as an attenuated form of psychosis to being considered a risk factor for its development, especially if combined with other risk factors (e.g., family history), which does not irrevocably lead to psychosis. This would explain the normal changes that take place in the symptomatology of this phase, which contribute to its characteristic diagnostic instability.

As is described in section 4, the group of researchers from Melbourne (Yung, McGorry and collaborators) have established three high risk mental state subtypes: 1. Presence of attenuated psychotic symptoms (subthreshold); 2. History of brief and limited psychotic symptoms (Brief Limited Intermittent Psychotic Symptoms), and 3. Family history of psychosis and persistent reduction of prior functional level.²¹¹

The concept of prepsychotic intervention is controversial given that it can consider any symptoms present prodromal when they may not actually lead to the development of a psychotic disorder, a phenomenon called “false positive”. However, many people will need treatment for their attenuated, disabilitating or disturbing symptoms, regardless of long-term diagnosis. Duration of Untreated Illness (DUI) refers to the untreated period of the disorder, prior to the onset of a psychotic episode. A significant part of psychotic disorder-related impairment is established and accumulated in this phase, which can last between two and five years .²¹²

In this phase, the objective of treatment is to prevent, delay or minimize the risk of transition to psychosis. Interventions are usually aimed, on the one hand, at treating present symptoms, and, on the other, at attempting to reduce the risk of aggravating their severity or evolution to a first psychotic episode.

To do so, different types of treatment have been applied: combined psychological (cognitive-behavioural, supportive and psychodynamic therapies) and pharmacological (antipsychotics, antidepressants, anti-anxiety drugs) treatments in the context of traditional services or specific early intervention programs and services. The types of studies perform present several methodologies: prospective, controlled, randomized studies, amongst others.

It seems that offering people who meet high risk criteria at least one initial psychosocial treatment that includes the nine cognitive therapies, aimed at alleviating the anxiety and impairment of young people, and symptomatic pharmacological treatment, with antidepressants or ant anxiety-drugs, is justified. The information regarding the level of risk of developing future psychosis that should be shared with the patient and family has been discussed. An open approach characterized by exploration and guided by the patient and family’s need to know, works well, especially when many of these patients and relatives are aware and concerned about the risk. Overall, a firm and optimistic attitude towards treatment and the possibility of recovery in schizophrenia and psychosis should be adopted (level of scientific evidence IV).²¹³ However, one must not forget that only approximately 33 to 58% of this population will develop psychosis²¹⁴ and that the intensity, timeframe and length of the intervention have not been well-established. Therefore, no intervention should be aimed at interpreting symptoms as prodromes, but at indicating that there is a risk of psychosis. Treatment should be aimed at current suffering and symptoms (for example, depression, anxiety and insomnia, amongst others) and close follow-up of the course of the disease will be carried out. Stress factors that may be exacerbating symptoms will be addressed in an attempt to prevent or modify them, changing the threatening perception of these factors and decreasing the corresponding physiological reactions. Specific treatment for psychosis (e.g., antipsychotic medication, education on psychosis) should be initiated only at the onset of true psychosis.²¹⁵ There is still an ethical debate on the convenience or lack thereof of applying treatment in patients in whom psychosis has not been established.

The primary results derived from studies regarding this phase are:

1. There are individuals at increased risk of developing psychosis (level of scientific evidence Ib;^216,217 levels of scientific evidence III^218,219).
2. The review of available scientific evidence shows that pharmacological and psychological treatment are superior to placebo or mere surveillance in delaying the transition to psychosis (level of scientific evidence Ia;⁸ level of scientific evidence Ib.²¹⁶)
3. Additionally, specific early intervention programs obtained better results than unspecific treatments: decreasing or delaying the transition to psychosis, improving prepsychotic symptomatology and preventing social decline and stagnation (level of scientific evidence Ib;^{216,217,220,221} level of scientific evidence III.²¹⁸)

A	Specific early intervention programs are recommended given that they can reduce and/or delay the transition to psychosis.8,216
B	Specific early intervention programs are recommended to improve prepsychotic symptomatology and prevent social decline or stagnation.216-218,220,221
C	It is recommended to carefully approach current symptomatology and suffering, both with the patient and with the family, with an empathetic and hopeful attitude.213
C	It is recommended to develop early intervention programs with comprehensive pharmacological (depending on symptomatology) and psychosocial (psychological treatment, family interventions and recovery support) interventions.222
C	Antipsychotic medication should not be prescribed as standard procedure unless there is accelerated deterioration, a high risk of suicide, if treatment with any other antidepressant has not been effective or if increasing aggression and hostility endanger other people.42

7.1.2. First psychotic episode phase

The onset of a first psychotic episode can be sudden or insidious, but most patients present some type of prodromal phase which is characterized by a slow and gradual development of several signs and symptoms (social withdrawal, loss of interest in school or work, deteriorated personal hygiene and self-care, unusual behaviour, sudden episodes of anger, etc.), after which an affective or non-affective symptom may appear, a key feature of the active phase, enabling the diagnosis of first psychotic episode. This prodromal phase can last several day or weeks, but may sometimes persist for several months. The characteristics of this period usually reappear in new relapses.

It was observed that the time elapsed from the onset of the psychotic disorder and its diagnosis and therapeutic intervention was very long, a period that was called duration of untreated psychosis (DUP).²¹²

The objectives of treatment in this phase are:^213,222

1. To provide a supportive therapeutic relationship.
2. To transmit hope to patients and families.
3. To introduce the idea of disorder.
4. To help patients accept medication.
5. To request the family’s support and provide them with support too.
6. To prevent the patient from harming him/herself or others.
7. To reduce psychotic and associated symptomatology.
8. To manage disordered behaviour.
9. To attempt to restore prior functional level.
10. To offer treatment in the least coercitive and restrictive setting possible.

The primary interventions in the acute phase of a first episode are aimed at providing support and psychoeducation, and are focused on addressing immediate problems at the beginning of treatment instead of focusing on the patient’s past traumas or family dysfunction. Support requires conveying hope, respect and empathy that is recognized by the patient. The first step of treatment is to build a therapeutic alliance. Once this has been achieved, supportive therapy is based on a synchronized psychoeducational approach that is tailored to the patient’s level of comprehension. These approaches give the patient hope and a feeling of greater control over the disorder.²¹³

The main outcomes of the primary studies in this phase were:

- It is important to treat the disorder to reduce DUP, given that available scientific evidence provides better results. In this respect, delayed treatment initiation is associated with the non-recognition of prodromal or primitive symptoms of psychosis (level of scientific evidence III)²²³ and insufficient accessibility to treatment teams (level of scientific evidence IIb).²²⁴

- Shorter DUP has been associated with (level of scientific evidence IIb):²²⁵

1. Improved response to antipsychotics
2. Improved overall functioning (measured using GAF or GAS)
3. Improved social and vocational functioning
4. Higher probability of reaching response criteria
5. Improved quality of life

- A longer DUP has been correlated with higher severity of negative symptoms and decreased grey matter as has been determined in a study with volumetric NMR imaging. No correlations have been found with relapse risk and neurocognitive disturbances (level of scientific evidence IIb).²²⁵

- CBT shows more benefits than standard care in preventing the evolution of psychosis in early intervention, decreasing prescription of antipsychotic medication and reducing symptoms (level of scientific evidence Ia).⁸

- A study on patients presenting a first psychotic episode reported that supportive psychodynamic psychotherapy or an integrated intervention with assertive community treatment and multifamily group treatment yields better outcomes at one year of treatment, measured using the GAF scale, than standard care, but differences are not statistically significant (level of scientific evidence IIa).¹⁵²

- In studies on first episodes of psychosis (non-affective), treatment with early intervention teams, which integrate assertive community treatment, multifamily groups and social skills training, obtains better outcomes in terms of reduced family burden and increased satisfaction, when compared to standard care (level of scientific evidence Ib).¹⁵²

- Another RCT study which compared early intervention teams and standard care, better outcomes were obtained by the intervention group in terms of social and vocational functioning, satisfaction, quality of life and adherence to medication (level of scientific evidence Ib).¹³⁷

- Similarly, a review of studies on first psychotic episodes which compare multi-element programs (which include CBT or supportive therapy in addition to pharmacological treatment) with standard care, better outcomes are obtained with the former in terms of symptom reduction, fewer inpatient care days, better adaptation to the disease, decreased suicide risk and improved subjective assessment of quality of life (level of scientific evidence Ib).¹⁴²

- It is recommended to provide outpatient care to people in early phases of psychosis using service strategies that are as least restrictive and coercitive as possible: developing strategies to minimize the use of treatments against the will of the patient in early psychosis (e.g. home intervention, alternative residential setting), hospital services focused on young people and routinely divided into “classes”, day programs for young people, residential facilities aimed at young people with psychosis so that they can live independently (level of scientific evidence IV).²²²

Pharmacological intervention in a first psychotic episode

The current state of research on pharmacological intervention in the first psychotic episode does not yield sufficient scientific evidence to administer first or second generation antipsychotics. However, some studies seem to show that second generation antipsychotics lead to better adherence, whereas first generation ones have a higher dropout rate.^{112,121,122,124,226}

A	If there is no response to treatment or low adherence or persistent suicide risk, the use of clozapine is recommended.1
A	Initiate the administration of low dose second generation antipsychotics.1
C	A 24 to 48 hour antipsychotic-free observation period is recommended, but benzodiazepines may be used for anxiety and sleep disorders.1
C	If there is response to treatment, maintain treatment over a period of 12 months, and if there is symptom remission gradually reduce dose over a few months with close follow-up.1
C	If there is no response to treatment, assess the causes. If there is poor adherence, analyze the reasons, optimize the doses and provide help to improve compliance.1
C	If there is no response to treatment, switch to another second generation antipsychotic and assess outcomes over a period of six to eight weeks.1
C	If second generation antipsychotics are being used and there are side effects, the switch to a first-generation drug could be considered.1

Psychosocial intervention in a first psychotic episode

A	CBT is recommended for the prevention of psychosis progression in early intervention, reducing prescription of drugs and symptomatology.8
A	Treatments in early intervention teams or multi-element programs are recommended in first psychotic episodes (non-affective).137,142,157
C	Informative campaigns are recommended to help recognize prodromal symptoms in the general population, general practitioners and professionals involved with the population at risk.222
C	Very accessible detection teams are recommended to reduce DUP and its corresponding outcomes.42
C	Care should be provided in the least restrictive and coercitive settings possible, while ensuring the safety of the patient and family.222
C	Supportive family interventions are recommended in accordance with their needs.138
C	Intensive case management and community-based support services, coupled with psychoactive drugs and psychotherapy, are recommended for some patients with early onset schizophrenia.34

7.1.3. Recovery phase after the first episode

It is a high vulnerability phase that encompasses the period between the third to fifth year after having had a psychotic episode, comprising the so-called critical period.²⁰⁷

An optimum and continued treatment is indicated in this critical period in which vulnerability reaches its peak and in which personal, social and biological factors influence the future balance between disorder and wellbeing. Relapses are very common during the first few years following the onset of a psychotic disorder and vulnerability to relapses persists in about 80% of patients. The restoration phase of the first episode and the stabilization phase are included here.

Psychological and psychosocial treatment should be the central elements in the critical period and should be used to help in the resolution of persistent positive and negative symptoms, secondary morbidity management and promotion of recovery and positive mental health. Recovery efforts should emphasize the need to find sense in psychotic experience and develop a certain degree of “control” over the situation.²⁰⁶

The highest degree of disability occurs during the first few years, but after this time it tends to stabilize, so the level of functioning achieved two years after diagnosis is a good indicator of what the level of functioning will be fifteen years later.

However, services usually offer less intense treatment during the periods between acute phases, constituting an inadequate model to address the needs of patients who are in the critical period.

The objectives of treatment in this phase are:

1. To achieve realistic academic or employment objectives.
2. To develop social relationships and normal sexual development.
3. To provide support to achieve an independent life.
4. To promote the establishment of personal values and identity.
5. To provide adequate age-adjusted support to minimize the effects of the disorder in the patient’s life and empower him/her to successfully cope with challenges that favour development.
6. To limit suffering and negative consequences of psychotic behaviour.
7. To provide support for families.
8. To be sensitive to factors that may hinder adequate follow-up of treatment, such as the negative effects generated by an assessment or procedures that cause rejection, side effects of medications, stigma or other obstacles to a collaborative relationship.
9. To offer treatment for associated problems such as suicidal tendencies, depression, aggression, substance abuse, cognitive impairment, anxiety disorders, instead of simply assuming that they are secondary phenomena.
10. To reinforce the concept of biological illness.
11. To emphasize the need of drug and alcohol abstinence.
12. To obtain the commitment of the patient and his/her family to a cooperation process.
13. To provide continued support to treatment adherence.
14. To provide comprehensive psychoeducation focused on positive and negative symptoms.
15. To teach coping strategies.
16. To facilitate opportunities to reduce social withdrawal by means of group-based treatment.
17. To help rebuild self-esteem.
18. To provide social skills training.

Several studies support the scientific evidence indicating that early intervention programs in psychosis versus traditional approaches offer better outcomes in several areas:

- In these studies, some use CBT as part of their therapeutic offer obtaining the following outcomes at 18 months: improved social, vocational functioning and quality of life, and increased patient satisfaction and adherence to medication, but there are no differences in symptom improvement (level of scientific evidence Ib).¹³⁷

- In a study which compared a specialized team versus standard treatment, it was reported that comprehensive treatment significantly improved the situation of employment and studying. However, two more years were needed to obtain this type of benefit. The study recommended more research in this respect. Additionally, an improved overall condition was observed at two years (measured using GAF) and also greater continuity and adherence to treatment (level of scientific evidence Ib).¹³⁸

- In another study which assessed early intervention with the combination of different types of treatment, no statistically significant differences were reported in the improvement of the symptoms measured in the PANSS scale and the Calgary Depression Rating Scale (level of scientific evidence Ib).¹³⁷

- The need to promote research studies on the benefits of treatment with early intervention teams is evidenced. Some authors recommend using a fidelity scale to make studies comparable, as well as to assess the results of specific interventions.¹³⁸

Furthermore, these is scientific evidence indicating that psychosocial treatments improve outcomes in the treatment of the first psychotic episode in several areas and may aid symptomatic and functional recovery:

1. - Early implementation of CBT and supportive therapy boosts faster recovery and reduces symptoms more than standard intervention, and may have long-term (18 months) benefits on these symptoms (level of scientific evidence Ib).¹⁴²
2. - CBT obtains better outcomes than standard intervention in suicidal risk, hospitalization, symptom reduction, adaptation to the disease and quality of life (level of scientific evidence Ib).¹⁴²
3. - When comparing CBT with supportive therapy and standard treatment, CBT offers protection from future relapses in the next 18 months (level of scientific evidence Ib).²²⁷
4. - Patients who receive CBT present fewer residual symptoms than patients who only received standard treatment (level of scientific evidence Ib).⁸
5. - FI seems to prevent re-hospitalizations^138,142 and relapses¹⁴² and promotes better adherence to medication¹³⁸ (level of scientific evidence Ib).
6. - Family members and carers exercise a crucial role in the access to care of patients with a first psychotic episode (level of scientific evidence III).²²³
7. - Psychodynamic, cognitive-behavioural and non-psychodynamic supportive psychotherapy, combined with pharmacological treatment, improve the overall functioning of patients more than pharmacological treatment alone or in combination with other psychosocial interventions. The best outcomes are obtained with dynamic psychotherapy and cognitive-behavioural therapy (level of scientific evidence Ia).¹⁴⁹

In the specific area of cognitive rehabilitation, in which most of the scientific evidence established up until now is based on patients with chronic schizophrenia, recent research points to the importance of differentiating the different impaired areas in first episode patients, given that motor and executive functions seem to be less impaired than memory and attention in this profile. There are indications that it may be possible to achieve significant recovery and resolution of problems and executive functions within one year of treatment (level of scientific evidence IV).¹⁶⁹

In the area of occupational insertion of people with first episodes there is scientific evidence indicating that supported employment is the most effective method, with maintenance of outcomes over longer periods of time. In this approach, the educational and training settings should be granted the same importance (level of scientific evidence IIb).¹⁸⁴

The professional dedicated to occupational rehabilitation should help the patient search for training or employment, as well as maintain them when found (level of scientific evidence IIb;¹⁸⁴ level of scientific evidence Ib)²².

Pharmacological intervention in the recovery from a first psychotic episode

A	If there are relapses, identify their causes, differentiating whether they are due to poor adherence or in spite of satisfactory adherence. If it is due to poor adherence, restore treatment.1
A	If there are tolerance problems with second generation medication, especially weight gain or metabolic syndrome, offer the possibility of switching to a different second or first generation antipsychotic.1
B	If there are tolerance problems with second generation medication, especially weight gain or metabolic syndrome, offer the possibility of switching to a different second or first generation antipsychotic.1
C	If a first generation antipsychotic is being use, switch to a second generation one if response is not adequate or if there are tolerance problems.1
C	If the patient has relapsed despite good adherence to a first generation antipsychotic, switch to a second generation one. If the patient presents symptom remission, good quality of life, and has not presented tolerance problems to conventional medication, maintain its use.1
C	As a last resort the switch to a first generation depot medication can be considered. However, long acting second generation injectable drugs may be considered an alternative to clozapine when there is low or uncertain adherence, especially if the patient prefers this option.1
C	If there is no response to treatment or low adherence with frequent relapses, low dose first generation depot antipsychotics should be tried for a period of 3 to 6 months.1

Psychosocial interventions in the recovery from a first psychotic episode

A	Early intervention programs for psychosis are recommended over traditional approaches.137,138
A	Psychosocial interventions are recommended in the treatment of first episodes.8,138,142
B	Supported employment is recommended as the most effective method to promote occupational insertion of people with first episodes.184
C	Cognitive rehabilitation is recommended in patients with specific deficits, even though the objective should also include related functional deficits.169
C	It is recommended to provide high quality intensive biopsychosocial care in a continued and active manner during the critical years following the onset of psychosis, preferably from specialized early intervention programs which also include pharmacotherapy, psychoeducation, stress management, relapse prevention, problem solving, reduction of harm due to substance use, supportive counselling and social and occupational rehabilitation, as well as family intervention and cognitive therapy.42

7.2. Phases of Schizophrenia

The following section presents the general guidelines to follow for the treatment of schizophrenia according to the phases described in chapter 4.2 of the CPG.^4,47

7.2.1. Acute phase (or crisis)

The acute phase is characterized by an acute psychotic episode. The corresponding objectives are as follows:

1. To prevent the patient from suffering injuries.
2. To control disordered behaviour.
3. To decrease the severity of psychosis and associated symptoms.
4. To identify and resolve the factors that triggered the onset of the acute episode.
5. To quickly restore an optimum level of functioning.
6. To establish an alliance with the patient and his/her family.
7. To formulate short- and long-term treatment plans.
8. To put the patient in touch with an adequate post-hospital care service.

An initial comprehensive diagnostic study should be performed on each patient, including psychiatric and general medical clinical history, physical exploration and mental health examination. Systematic interviews can be conducted with family members and other people who know the patient well, given that many patients are unable to provide reliable accounts of their clinical history during the first interview. For more information on diagnosis and assessment, refer to chapter 5.1 of this CPG.

The factors which trigger symptom relapse should be considered, such as compliance of antipsychotic treatment, substance abuse and stressful life events. One must not forget that relapses are frequent in the natural course of the illness, even when there is good adherence to treatment. When poor therapeutic compliance is suspected, it is recommended to analyze the reasons and taken them into account in the treatment plan.

In this phase it is important to pay special attention to the existence of suicidal potential. Prior suicide attempts, depressed mood, and suicidal ideation may be prognostic factors of a subsequent suicide attempt (level of scientific evidence Ib). It is recommended to perform similar assessments in terms of the possibility of dangerous and aggressive behaviour towards others.⁴

 

Pharmacological intervention in the acute phase

B	Pharmacological treatment should be initiated immediately, unless it interferes with diagnostic assessment, given that acute psychotic aggravation is associated with emotional discomfort, disturbances in the patient’s life and considerable risk of behaviours that may endanger the life of the patient and others4
C	Patients and family members should be completely informed on the benefits and risks of pharmacological therapy and advised when choosing antipsychotic medication; the services of interpreters or cultural mediators should be used when necessary. In the case of not being able to openly discuss treatment options with the patient, as occurs in the case of some acute episodes, oral second generation medication should be the treatment of choice due to the lower risk of extrapyramidal symptoms.1
C	When choosing a certain antipsychotic medication, the patient’s prior response to treatment, the side effects profile, preferences for a certain drug based on prior experience and the foreseen administration route should be taken into account.228 The recommended doses of antipsychotics have been described in the corresponding tables of this CPG.
C	The key principle is to avoid the first choice use of drugs that tend to weaken future adherence due to the development of side effects. The immediate objective is not only the reduction of aggression, agitation and risk but also to make the patient feel subjectively better and calmer with good tolerability.1
C	The first step of clinical management of resistant schizophrenia is to establish that antipsychotic medications have been adequately used in terms of dose, duration and adherence. Other causes of poor response should be considered in clinical assessments, such as the incorrect use of comorbid substances, poor adherence to treatment, simultaneous use of other prescribed drugs and physical disease.3
C	If schizophrenia symptoms do not respond to first generation antipsychotics, the mental health professional and patients should consider the use of a second generation antipsychotic prior to the diagnosis of treatment-resistant schizophrenia or a trial with clozapine.3

Frequently other psychoactive drugs are added to antipsychotic drugs when patients continue to present active psychotic symptoms: lithium, carbamazepine, valproic acid and benzodiazepines; however, the efficacy of these coadjuvant treatments has not been proven in randomized clinical trials.⁴⁷

Furthermore, coadjuvant medications can be used to boost the response in patients who present insufficient response (especially with affective symptoms), to reduce violent behaviour, or in disorders associated with schizophrenia: antidepressants if there are persistent depressive symptoms, benzodiazepines if there is anxiety or agitations (lorazepam or clonazepam).

Drugs for the treatment of extrapyramidal symptoms or other side effects are also used. Their use depends on the severity or intensity of symptoms and on the consideration of other possible strategies such as the reduction of antipsychotic dose or switching of antipsychotic. In terms of the prophylaptic use of antiparkinson medication, the following factors should be taken into account: the tendency of antipsychotic medication to cause extrapyramidal side effects, the patient’s preferences, history of extrapyramidal side effects, other risk factors (dystonia), and risk factors and possible consequences of anticholinergic side effects.

C

It is recommended that the use of medications such as lithium, carbamazepine, valproic acid or benzodiazepines be reserved for cases where clozapine is not appropriate in treatment-resistant patients due to poor efficacy, side effects, patient preference or likely lack of compliance of the surveillance program.25

Use of ECT in the acute phase

ECT is always a second choice treatment in schizophrenia,⁴⁷ indicated after the failure of antipsychotics; the most frequent indications are: catatonic schizophrenia, severe cases that present intense agitation and/or confusion, contraindications to antipsychotics (due to the possibility of causing neuroleptic malignant syndrome), resistant secondary depression and resistant schizoaffective disorders.¹²⁵

Available data suggest that antipsychotic treatment should be maintained during and after ECT.

Psychosocial interventions in the acute phase

Psychosocial interventions in this phase are aimed at reducing relationships, environments or episodes in life which are too overstimulating or stressful and to promote relaxation by means of simple, clear and coherent communications and expectations in a structured and predictable environment, with low functional demands and supportive, tolerant, non-demanding relationships with all the professionals who are involved in the management of this phase of the disorder.

The patient should be encouraged to collaborate with the psychiatrist in the choice and adjustment of medication and other treatments. The psychiatric should initiate a relationship with family members, who are usually concerned about the patient’s disorder, his/her disability, prognosis and hospitalization. Training meetings that teach the family how to cope with schizophrenia are recommended, as well as referral to patient and family associations.

Scientific evidence in patients in acute phases indicates that CBT produces a faster effect than standard treatment, but not when compared with supportive.8 However, there is scientific evidence in this phase determining that CBT coupled with standard care can accelerate recovery and hospital discharge (level of scientific evidence Ib).¹

A	CBT is recommended in the acute phase, coupled with standard care, to accelerate recovery and hospital discharge.1

Additionally, the following aspects should be considered in this phase:^47,70

1. Outpatient treatment, if the patient’s symptomatology can be tackled on an outpatient basis, the patient has a contained environment and both he/she and the family prefer it.
2. Inpatient treatment if several factors are present: intensity of psychopathology, assessable risk of self- or hetero-aggression, general medical pathology for which outpatient management is not suited, psychosocial or family factors.
3. The possibility of admittance into an inpatient or day care unit (day hospital), depending on the assessment of the patient’s state, the need for specific treatments, family function, social support, patient and family preferences, and therapeutic resources available in the community.

7.2.2. Stabilization phase (or postcrisis)

The stabilization phase or postcrisis corresponds to the 6-12 months following an acute episode. During this phase the patient is recovering functionality and adjusting to an increasingly more demanding environment.

The objectives of treatment in this phase are:

1. To reduce the stress experienced by the patient as much as possible.
2. To decrease the probability of relapse and symptoms.
3. To continually reduce symptoms and consolidate their remission.
4. To favour the recovery process.

If the patient has required inpatient care, once he/she has been discharged gaps in the continuity of treatment should be avoided. A prior appointment should be made with the corresponding mental health centre and the patient should be aided in establishing realistic objectives to prevent stress or an increased risk of relapse, avoiding inadequate pressure to reach an excessive degree of occupational and/or social function.

Pharmacological treatment in the stabilization phase

C

Due to the risk of fast relapse in the postcrisis phase, the discontinuation or reduction of antipsychotic pharmacological treatment initiated in the acute phase should be avoided. The continuation of treatment over a period of one or two years after a crisis should be discussed, when appropriate, with the patient and family.3

C

If possible, in patients with complete remission antipsychotic medication should be administered over a period of at least 12 months and a subsequent attempt should be made to gradually discontinue medication over a period of at least several weeks. Close monitoring should be followed by specialist follow-up over the next 12 months and any relapse should be promptly identified and treated. Patients should not be referred to primary care exclusively, as shared health care is the best option in all these phases1

Psychosocial interventions in the stabilization phase

In this phase, supportive psychosocial interventions should be less structured and guided than in the previous phase. Furthermore, education on the course and consequence of the disease should be initiated for patients and maintained for family members.

According to reviewed scientific literature, the recommendations for psychosocial interventions in this phase can be summarized as follows (see chapter on Psychosocial Interventions):

A	Health education programs are recommended in this phase given that they have been proven effective at teaching self-management of medication (maintenance antipsychotic treatment, side effects, etc.), self-management of symptoms (identification of the first signs of a relapse, their prevention, and refusal to consume drugs and alcohol), and basic social skills.229-231
A	The application of CBT is recommended for the treatment of positive and negative symptoms that are resistant to antipsychotics.232
A	CBT is recommended for the treatment of positive symptoms in schizophrenia,134 especially hallucinations.7
A	CBT is recommended as a treatment option to aid in the development of insight.7
A	CBT is recommended as a treatment option to increase adherence to treatment.7
A	Patient psychoeducation is recommended given that it reduces relapse risk, probably by improving adherence, improves the patient’s satisfaction with treatment and improves knowledge.1
A	FI therapy is recommended in patients who are moderately or severely disabled and especially in patients with long evolution of the disease. In patients with recent onset of the disorder each situation should be individually assessed.11,12
A	FI should be offered to families who live or are in contact with patients with schizophrenia, especially those who have relapsed or present relapse risk and also in those cases with persistent symptomatology.3
A	FI programs should include family members of patients with homogeneous diagnosis, enable the patient’s participation and ensure that he/she is well-informed. FI should take place over a period of at least six months.12
A	FI programs are recommended to reduce family burden, improve the patient’s social functioning and decrease economic cost.11,12
A	Psychoeducational FI, based on the management of expressed emotion, is recommended to prevent relapses and improve disease prognosis(its effects are maintained at 24 months).11-16
A	Programs should always include information for families regarding the disease and different strategies such as stress coping techniques or problem solving training.17,18
A	The application of social skills training (based on the problem-solving model) is recommended in patients who are severely or moderately disabled, given that it is effective in terms of social adaptation and its effects are maintained after two years.21
B	Referral to patient and carer social networks is recommended given that support groups are effective at providing support to the family.1
C	It is recommended to develop a therapeutic alliance based on emotional support and cooperation, given that it plays an important role in the treatment of people with schizophrenia.9
C	Supportive therapy is not recommended as a specific intervention in the normal care of people with schizophrenia if other interventions with proven efficacy are indicated and available or if the patient expresses his/her preferences for this type of psychotherapy9
C	Supportive psychotherapy focused on reality, with realistic objectives, is recommended for patients who are moderately disabled and stable or intermittently stable.28

The continuity of care services is important for the prevention of relapses. In the case of inpatients, it is recommended to have a consultation with a psychiatrist prior to initiating outpatient treatment. If the patient must live in an out-hospital residence, the consultation should be made before hospital discharge.⁴

B	Adaptation to the community can be facilitated by establishing realistic objectives and avoiding excessive pressure on the patient to achieve high employment and social performance.4

At an out-hospital level, it is very important to maintain a certain level of activity to improve social functioning and to convey feelings of hope and progress to the patient and family.⁴

7.2.3. Stable phase (or maintenance phase)

During this phase patients may not have any symptoms at all or present symptoms such as tension, irritability, depression, negative symptoms and cognitive deterioration. Some patients may still present positive symptoms, but to a lesser degree than in the acute phase (the patient may present hallucinations, delusions or disordered behaviour).

The therapeutic objectives in this phase are:

1. To maintain symptom remission or management.
2. To preserve or improve functionality and quality of life.
3. To effectively treat increasing symptoms and relapses.
4. To carry out continued follow-up of treatment side effects.

In this phase the administration of antipsychotics should take the following aspects into account:⁴⁷

1. To establish a long-term treatment plan to reduce side effects and relapse risk to a minimum.
2. In patients with a history of poor compliance, long acting depot drugs are an option given that these drugs tend to result in improved long-term evolution of these patients.
3. The significant reduction or discontinuation of antipsychotics can cause almost immediate aggravation.
4. In other patients with minimal psychotic symptoms medication can have a prophylaptic effect.
5. The dose of maintenance medication should be established acknowledging that excessively high doses can produce extrapyramidal side effects (akinesia or akathisia) that may hinder adaptation to the community and reduce treatment compliance.
6. During chronic treatment, subtle akinesia may develop in the form of decreased spontaneous movement, reduced conversation, apathy and difficulties initiating any activity. It is hard to differentiate from negative deterioration of schizophrenia and depression symptoms.
7. Very low doses of antipsychotics may be associated with increased compliance, improved subjective state, and improved adaptation to the community, but the higher risk of relapse and exacerbation of the most characteristic symptoms of schizophrenia should be acknowledged.

On the other hand, during this period psychosocial interventions are effective complementary treatment to pharmacological treatment. Specific psychosocial instructions such as re-education in terms of basic daily life skills, social skills training, cognitive rehabilitation and the initiation of occupational rehabilitation can be introduced. It is also important to provide health education aimed at the patient and his/her family to increase knowledge on the first signs of relapse.

In the patient agrees, it is useful to maintain contact with people closest to the patient given that they have more possibilities of detecting the appearance of symptoms, stressful factors and events which could increase relapses or interfere with functional restoration.⁴

Pharmacological intervention in the stable phase

A	Coadjuvant medication is frequently prescribed for comorbidity in patients with schizophrenia who are in the stable phase. Major depression and obsessive-compulsive disorder may respond to antidepressants.4
C	Withdrawal of antipsychotic medication should be carried out gradually while performing regular monitoring of signs and symptoms that may indicate potential relapses.3
C	A complete physical examination, including weight, blood pressure, lipid profile, ECG and blood fasting glucose should ideally be performed in collaboration with the primary care physician at least once a year. Routine screening of cervical and breast cancer should be carried out in women. In patients over the age of 40, it is important to consider new symptoms and perform screening tests for the common types of cancer. If there are no guarantees that primary care will carry out this type of monitoring, it should be placed in the hands of the psychiatrist.1

Psychosocial interventions in the stable phase

As was presented throughout the CPG, psychosocial interventions that are effective in the stabilization phase are also effective in the stable or maintenance phase (see chapter on Psychosocial interventions). The following interventions can also be considered:

A	Supportive psychotherapy for problem solving is recommended given that it significantly reduces relapses and boosts social and occupational function when added to medication in patients treated on an outpatient basis (level of scientific evidence Ia).233-235
A	Cognitive rehabilitation is recommended in the patient’s social environment given that it has been shown to be effective (in contrast to traditional cognitive rehabilitation) in the prevention of relapses and social adaptation.20
A	It is recommended to provide occupational support to patients who are moderately or mildly disabled, given that it has been shown to be effective in the obtention of normalized employment.24,25
A	In patients with early onset schizophrenia social skills techniques are recommended, given that they result in better outcomes than supportive techniques.21
A	The application of cognitive rehabilitation, in all its modalities, is recommended as a technique that improves cognitive functioning in a wide range of clinical conditions of the patient with schizophrenia.19
A	Patients with schizophrenia should be encouraged to find employment. Mental health specialists should actively facilitate this process and specific programs incorporating this intervention should be widely established.1
A	The best outcomes in occupational insertion of people with schizophrenia are obtained with supported employment programs, when compared to other occupational rehabilitation interventions.22,23,181
B	The strategies to tackle social stigma and discrimination of the mentally ill are more effective when education includes contact with schizophrenic people who share their story.2
B	An evidence-based format of training in abilities for daily living should be available to patients who have difficulties in daily functioning.2
C	If possible, patient preferences in terms of housing and resource selection should be favoured, acknowledging the right of the patient to live in an environment that is as normalized as possible, articulating the necessary training programs and providing proper support so that the patient can access and remain in the aforementioned setting.27

7.3. Specific situations

This chapter addresses some specific situations that may be related with schizophrenia, such as substance abuse, suicide, violent behaviour, depressive symptoms, or homeless patients. In order to guarantee an adequate intervention it is necessary to treat not only specific symptoms of schizophrenia but also to carefully assess the conditions described.^4,47

7.3.1. Substance use-related disorders

Substance use-related disorders are an important morbidity factor when they develop in combination with schizophrenia. It is estimated that up to 40% of people with schizophrenia engage in substance abuse or present dependence, long-term incidence increasing throughout life (60% in some studies).

Substance use-related disorders are associated with more frequent and prolonged inpatient care, and with other negative outcomes, such as homelessness, violence, imprisonment, suicide and HIV.

C

It is recommended that treatment objectives in patients with this associated pathology mirror the objectives of treatment of schizophrenia with no associated pathology, but adding the objectives relating to substance use problems, such as harm reduction, abstinence, relapse prevention and rehabilitation.47

The key issue for the application of treatment in this population is to develop an approach that integrates treatment of substance use-related disorders and schizophrenia. At present, there are many programs that provide this integration by means of interdisciplinary teams with experience in the treatment of schizophrenia and substance use-related disorders. Antipsychotic drugs can be used at normal doses, but patients should be informed that the combined use of antipsychotic medication and alcohol or other substances can increase sedation and lack of coordination. When prescribing drugs, the psychiatrist should take into account the possibility that the convulsive threshold may decrease when using antipsychotic drugs, as well as the possibility that patients may engage in benzodiazepine and anti-Parkinsons drug abuse. Rarely, antipsychotic drugs may trigger convulsive crises during alcohol or benzodiazepine abstinence.

Disulphiram may entail a certain risk for patients with schizophrenia who engage in alcohol abuse, given that it can trigger a psychotic episode. Given that this drug has harmful negative effects when taken with alcohol, it should only be used in patients with reasonably good judgement, who adhere to treatment and have adequate contact with reality.

Naltrexone is a drug that seems to reduce alcohol craving and is used to treat opiate dependence, but it has not been studied in depth in patients with schizophrenia. New studies are necessary to assess the use of naltrexone on this population.

The therapeutic approach should be integrated and take into account the patient’s cognitive deficits and limited tolerance to stress. Overall, groups should be supportive and psychoeducational. The length and frequency of group sessions should be regulated in terms of the patients’ attention periods and tolerance. Therapists should actively maintain the group structure and limit the degree of stress, avoiding direct confrontation of patients, which is common in programs aimed at substance abuse.

Patients should understand that they have two complex chronic disorders that, together, lead to worse prognosis than each would have by itself.

Some studies indicate that support and acceptance programs for these patients yield better outcomes than confrontation programs aimed at patients who only present addictive pathology (level of scientific evidence Ib).⁴⁷ Even if the patient has not achieved complete abstinence, he/she should not be excluded from interventions recommended for patients with schizophrenia or for patients with disorders due to substance use.

7.3.2. Schizophrenia and suicide

Suicide is the leading cause of premature death amongst patients with schizophrenia. In contrast to the general population, the probability that people with schizophrenia will die from suicide is nine times higher. Up to 30% of patients with schizophrenia attempt suicide, and between 4 and 10% die after the attempt. The estimated percentage of suicidal behaviour in people with schizophrenia ranges from 20 to 40%.

Knowledge on suicide risk factors associated with schizophrenia is limited. Some of these risk factors are shared by the general population: male gender, Caucasian race, being single, social isolation, depression or hopelessness, unemployment, substance dependence, recent losses, and a personal and/or family history of suicide attempts.

Other specific risk factors are, on the one hand, youth, with mean age 33 years, whereas in the general population the highest risk corresponds to ages over 65; and on the other hand, the period encompassing the first six years after the first hospitalization, having high IQ, chronic course and progressive deterioration with exacerbations, or perceived loss of functional capacities. Other additional risk factors are the presence of suicidal ideas, auditive hallucinations and recent hospital discharge.

C	It is recommended to increase the frequency of outpatient visits in patients who have recently been discharged from the hospital, given that it is a vulnerable period for the patient.47

It is possible that the increased suicide risk in schizophrenia occurs in the remission phase. Associated depressive symptomatology is characterized more by hopelessness, cognitive impairment and deterioration, than by symptoms that can be diagnosed as major depression.

Many patients present one or several of these risk factors, but do not commit suicide or attempt to commit suicide, whereas others may do it unexpectedly without prior signs of significant risk. It is not possible to predict if a specific patient will commit suicide.

Overall, early suicides coincide with clear awareness of disabling disease and after remission of acute symptomatology. Later suicides coincide with impairment that is especially social; overall they are premeditated suicides even though they may have been triggered by a stressful event.

A significant percentage of the suicides committed by patients with schizophrenia take place during a remission period after five to ten years of illness. It seems to be a reflection of perceived hopelessness in terms of their own pathology, which can reappear without any warning signs. Family members should be aware of this possibility. Even with the best of care, it is likely that a percentage of patients with schizophrenia will die from suicide.

However, it is essential to assess the risk of suicide initially and on a regular basis as part of the psychiatric evaluation of the patient. Suicide ideas or threats should be assessed in the context of the patient’s clinical history provided by him/herself and family members and the current therapist, if possible.

Some data indicate that both first and second generation antipsychotic decrease the risk of suicide. However, clozapine is the drug that has been most studied, and it has been reported that it reduces suicide rates and persistent suicidal behaviour (level of scientific evidence Ib).⁴

C

During inpatient care it is essential to adopt precautions to avoid suicide and closely monitor suicidal patients.47

C

Patients who have been deemed to have high suicidal risk should be put into inpatient care, and the necessary measure to avoid suicide should be applied. It is important to optimize pharmacological treatment of psychosis and depression, and to address the suicidal inclination of the patient directly, with an empathetic and supportive approach. Close surveillance should be carried out on vulnerable patients during periods of personal crisis, environment changes or periods of hardship or depression over the course of the disease.47

A meta-analysis of four randomized clinical trials, already mentioned in the section on Modalities of care and intensive follow-up in the community of this CPG, assessed the effectiveness of community mental health teams versus conventional care in the treatment of any type of severe mental illness. One of the outcomes analyzed was suicide. Results indicated that treatment with community teams is superior in terms of better acceptance of treatment, reduced hospitalizations and prevention of deaths by suicide (level of scientific evidence Ia).²⁹

A	Treatment by community mental health teams is recommended in severe mental disorders to reduce deaths by suicide.29
C	When discharged, the patient and his/her family members should be advised to stay alert to warning signs and initiate prevention measures if suicidal ideas reappear.4
C	When a patient has been recently discharged, it is recommended that he/she undergoes more frequent outpatient management. The number of visits should be increased in times of personal crisis, significant changes in the patient’s surroundings, increased discomfort or depression that is accentuated over the course of the disease.4

7.3.3. Violent behaviour

Violent behaviour can appear in patients with schizophrenia and its incidence varies in terms of the more or less acute or severe nature of the patient’s psychosis. General risk factors are: a history of prior arrests, substance use, presence of hallucinations, delusions or strange behaviours, neurological deterioration, male gender, low socioeconomic class, limited studies and being single.

The identification of risk factors of violence and violent ideas is part of the standard psychiatric assessment. The assessment of a patient who may be violent requires the application of safety measures (additional staff). If a patient represents a serious threat to others, the psychiatrist should use his/her own judgement, in accordance with legal regulations, to protect those people from foreseeable harm. In patients who present an imminent risk of violent behaviour, assessment should be carried out for possible inpatient care and, if indicated, apply precautionary measures at the moment of hospital admittance.

Treatment of aggression can often be performed using behavioural and maintenance therapy in a restricted setting. Antipsychotic medication is the core of treatment, but the use of anticonvulsants, lithium and propanolol at high doses has also been described, together with the possible favourable effect of clozapine.

Emergency treatment of violence in schizophrenia may include sedation (using benzodiazepines such as diazepam in intramuscular doses of 10-20 mg,²³⁶ or in combination with 5 mg of intramuscular haloperidol), and a restricted setting. The use of a restricted setting should be an emergency measure applicable when other less restrictive measures have failed, and the patient should be seen with the frequency required to adequately monitor changes in the physical or mental state. Restrictions should be gradually removed as the risk of self- or hetero-aggressiveness decreases.

Ethical regulations^j stipulate that restrictive measures can only be applied if they stem from a therapeutic plan and the following criteria are met:

1. A clinical indication that is individualized and limited to a certain period of time.
2. A prior explicit medical order need. In an emergency situation and should any nursing action be taken, it should promptly be reported to the referral physician for final approval.
3. It should be applied in exceptional situations and with an exclusively therapeutic objective which is based on the principle of the patient’s benefit.
4. The previous measure should be reasonably effective and clearly yield more benefits than risks.
5. There are no other less restrictive means in order to offer the patient the treatment he or she requires.
6. In no case shall this measure be applied as punishment or a form of control.
7. In no case shall this measure respond to extra clinical motives, such as to compensate for insufficient staff.
8. Actions should be carried out by health care staff with adequate level of knowledge and training in the care of these patients.
9. The patient should be provided with adequate prior information and, if possible, his/her consent should be sought. The family will also be informed and encouraged to collaborate in the treatment process.
10. Actions will be performed with the utmost dignity and respect towards the patient, safeguarding and upholding his/her constitutional rights.
11. Restriction should always be based on the patient’s decreased mental competence due to his/her psychopathological state. The idea that it is being done “for the patient’s own good” is not acceptable if the patient acts responsibly and competently.
12. The restrictive measures indicated shall always appear in medical orders of the clinical history.
    

7.3.4. Depressive Symptoms

Depressive symptoms frequently develop in the psychopathology of schizophrenia and may occur in all of its phases. When they occur in the acute phase of the disorder a differential diagnosis with schizoaffective disorder should be performed. The differential diagnosis should take into account the influence of side effects of antipsychotic medications, personal attitudes or substance use. The addition of an antidepressant during the acute phase should be performed with caution given that it may exacerbate psychotic symptoms. Treatment should be performed sequentially.

Depressive symptoms that persist or appear after the remission of psychotic symptoms are called “residual” or “secondary” (postpsychotic) depressive symptoms and they have been shown to respond to antidepressant treatment.

As with negative symptoms of a deficitary state, secondary depression should be differentiated from other possible causal disorders:⁴⁷

1. General medical disorders.
2. Substance-induced disorders.
3. Extrapyramidal side effects of antipsychotics: akathisia and akinesia. This “depression” may disappear by decreasing the antipsychotic dose or adding an anticholinergic drug.
4. Demoralization due to the effect of the illness and “situational” reactions of personal crises or changes in the surroundings which require more surveillance of the patient and an empathetic and supportive approach.

Some data suggest that depressive symptoms are reduced with the use of antipsychotic treatment. Some comparative trials have reported that second generation antipsychotics could be more effective at treating depression than first generation drugs (level of scientific evidence Ib). However, some scientific evidence also suggests that this apparent antidepressant effect could be related with the low probability of neurological side effects of second generation antipsychotics (level of scientific evidence IV).⁴

A	Second generation antipsychotics are recommended for the treatment of depressive symptoms.4
B	A major depression episode during the stable phase of schizophrenia is an indication for treatment with an antidepressant drug.2
B	It is possible to add antidepressants as complementary treatment to antipsychotics when depressive symptoms meet the syndromic criteria of major depression or are severe, causing significant discomfort or interfering with the patient’s functionality.4

7.3.5. Homeless patients

Different studies and settings present a prevalence of schizophrenia in homeless patients ranging from 2 to 43%; in Spain it ranges from 18 to 26%.²³⁷

In patients with schizophrenia the risk factors for becoming homeless after hospital discharge are, according to a longitudinal study: comorbidity with a substance use-related disorder, persistent psychiatric symptoms –for example, BPRS > 40- and decreased overall function –for example, GAS < 43- (level of scientific evidence III).²³⁸

It would not be reasonable to assume that the problems of homeless patients with schizophrenia could be resolved exclusively by mental health services. However, mental health professionals can detect patients with an increased risk of becoming homeless and act preventively by tackling known risk factors.

B	Follow-up of patients after hospital discharge is recommended. Professionals should remain alert to comorbidity due to patient’s substance use, psychiatric symptoms and overall function to prevent the risk of patients becoming homeless.47

In regards to the clinical assistance to homeless patients, this CPG includes what has been reported by previous studies given that there is insufficient evidence that assesses the efficacy of these interventions and whilst the pertinent studies are awaited.⁴⁷

C	Treatment and support in transition to housing are recommended for homeless schizophrenic patients.47