Il disturbo Schizoaffettivo: criteri diagnostici e trattamento Prof. Mauro Mauri Clinica Psichiatrica Università di Pisa

Do schizoaffective disorders exist all? More than 100 years ago Kraepelin proposed a very pratical and persuasive solution to a longstanding problem in clinical psychiatry. To reduce heterogeneity by splitting the perplexing variety of psychopatological signs and symptoms, of patterns of deviant behavior and experiences, of short- and long-term course and outcome of functional disturbances into two major groups: Dementia Praecox Manic-depressive illness Acta Psychiatr Scand 2006: 13:369-371. Editorial

In this way, he created the so-called ‘Kraepelinian dichotomy’, which turned out to be clinically useful for subsequent decades. However, he himself got skeptical subsequently if this simplistic solution really worked in pratice as the number of ‘cases in-between’ were too numerous. Do schizoaffective disorders exist all? Acta Psychiatr Scand 2006: 13:369-371. Editorial

Schizoaffective Disorders In 1933, Kasanin first coined this term… Do schizoaffective disorders exist all? Acta Psychiatr Scand 2006: 13:369-371. Editorial

About 70 years ago, the concept of schizoaffective disorders emerged from difficulties in practicing Kraepelin’s dichotomy by separating schizophrenia and affective disorders. Do schizoaffective disorders exist all? Acta Psychiatr Scand 2006: 13:369-371. Editorial

Schizoaffective Disorders Although originally related to ‘reactive psychoses’ in the Scandinavian tradition, the term became transformed to indicate the intraindividual co-occurrence of both severe affective as well as severe psychotic syndromes, which did not fit in either of Kraepelin’s categories. Langfeldt G. The prognosis in schizophrenia and the factors influencing the course of the disease. Acta Psychiatr Neurol Scand 1937; Suppl. 13:1–228.

Schizoaffective Disorders The widespread use of this term reflected the clinical need to consider border-cases separately. Many clinicians are probably motivated to use this category because of implications on the course of Illness. Do schizoaffective disorders exist all? Acta Psychiatr Scand 2006: 13:369-371. Editorial

Orientamenti attuali Le evidenze empiriche attualmente disponibili sembrano indicare che i disturbi schizoaffettivi costituiscono un gruppo eterogeneo di condizioni morbose. Non ha senso affermare che essi, nel loro complesso, rappresentino sempre delle varianti della schizofrenia, oppure delle varianti dei disturbi affettivi maggiori, oppure una terza psicosi.

Definizione L’espressione “disturbo schizoaffettivo”(1) può essere usata per identificare l’una e/o l’altra delle seguenti situazioni cliniche: Comparsa successiva e indipendente di una sindrome affettiva e di una schizofrenica (dist. schizoaffettivo tipo I) Comparsa contemporanea, nel medesimo episodio, di una sintomatologia di tipo affettivo e una di tipo schizofrenico (dist. schizoaffettivo tipo II). Maj e Perris, 1985

I Disturbi Schizoaffettivi: Modelli Teorici 1.Varietà atipiche della schizofrenia 2.Varietà atipiche dei disturbi affettivi maggiori 3.Terza Psicosi 4.Continuum Psicotico 5. Manifestarsi contemporaneo di schizofrenia e di un disturbo affettivo maggiore.

Modelli interpretativi dei Disturbi Schizoaffettivi Modello Binario o dicotomico neo-kraepeliniano Modello della terza psicosi Modello del continuum psicotico I disturbi schizoaffettivi sono sempre varietà atipiche della schizofrenia o dei disturbi affettivi maggiori Almeno una parte dei disturbi schizoaffettivi costituisce un’entità nosografica distinta dalla schizofrenia e dai disturbi affettivi maggiori I disturbi schizoaffettivi occupano la parte intermedia di uno spettro ai cui estremi si pongono le forme tipiche di schizofrenia e di disturbo affettivo maggiore

Il problema della natura dei disturbi schizoaffettivi e dei loro rapporti con la schizofrenia e con i disturbi affettivi maggiori è tuttora controverso.

Schizophrenia Spectrum …Schizophrenia Spectrum almost certainly includes schizoaffective disorders (and) should probably also include at least the psychotic forms of mania and depression. (Andreasen, 1995) 7

I sistemi nosografici hanno proposto nel tempo criteri ora rigidi e restrittivi, ora ampi e comprensivi, senza raggiungere una delimitazione accettabile sul piano psicopatologico e clinico. (TSUANG e LOYD, 1986)

Seppure gli estensori delle varie edizioni del DSM abbiano inteso segnare confini netti tra psicosi bipolare e schizofrenica, il problema rimane irrisolto con le sue caratteristiche storiche.

Spectrum of Endogenous Psychoses Affective Psychoses Schizoaffective Disorder Schizophrenia Bipolar Disorder Psychotic Depression Bipolar Type Depressive Type Depressive Episodes Negative Sxs After Kraepelin E, 1921

Schizophrenia with Bipolar Spectrum Bipolar Spectrum with Psychotic Features Schizophrenia Spectrum (H.Y. Meltzer, 1995)

Schizophrenia Spectrum Schizoaffective Disorder Bipolar Psychotic Disorder Psychotic Depression Schizophreniform Disorder Schizotypal Personality Disorder Schizoid Personality Disorder Paranoid Personality Disorder Meltzer, 1996 5

Bipolar-Schizophrenia continuum Manic-depression and schizophrenia are 2 distinct disorders. (Kraepelin’s) Proponents of the bipolar continuum theory support the concept of an expanded psychiatric continuum ranging from unipolar to bipolar disorder, to schizoaffective psychosis, all the way to schizophrenia. Much of the evidence supporting the continuum concept is based upon genetic, biochemical, and pharmacologic findings. Hans-Jürgen Möller, M.D Bipolar Disorder and Schizophrenia: Distinct Illnesses or a Continuum? (J Clin Psychiatry 2003;64[suppl 6]:23–27)

Continuum Psicotico Il tentativo di tracciare una linea di demarcazione genetica tra disturbi schizofrenici e disturbi affettivi è fallito. Crow, 1990

Family linkage studies Clinical, familial, and, more recently, genetic linkage studies suggest that overlapping genetic susceptibility might contribute to both schizophrenia and bipolar disorder. Franck Schürhoff, M.D. et al.,Familial Aggregation of Delusional Proneness in Schizophrenia and Bipolar Pedigrees (Am J Psychiatry 2003; 160:1313–1319)

Family linkage studies Overlap between bipolar disorder and schizophrenia has long been noted clinically. About 9% of people with schizophrenia have manic syndromes and 25% have depressive syndromes psychotic symptoms—hallucinations and delusions—occur in 58% of people with bipolar I disorder. The existence of a diagnostic category incorporating elements of mood disorder and schizophrenia—schizoaffective disorder—reflects the difficulty that occasionally arises in distinguishing the two illnesses. Evidence for overlapping heritability of bipolar disorder and schizophrenia has emerged from genetic epidemiologic studies James B. Potash, Suggestive Linkage to Chromosomal Regions 13q31and 22q12 in Families With Psychotic Bipolar Disorder (Am J Psychiatry 2003; 160:680–686)

…la mappatura di regioni “sospette” evidenzia una sovrapposizione delle regioni di linkage per la Schizofrenia e i Disturbi Affettivi… questi risultati fanno ipotizzare l’esistenza di geni condivisi da entrambi i disturbi e la possibilità che questi geni possano contribuire alle basi molecolari delle psicosi funzionali. Wildenauer, 1999

This notion is supported by various independent findings. High degree of genetic transmissibility.Gene mapping for both diseases is in its early stages, but certain susceptibility markers appear to be located on the same chromosomes. Bipolar disorder and schizophrenia also demonstrate some similarities in neurotransmitter dysfunction. As further indirect evidence of a possible association, many newer atypical antipsychotic agents approved for the treatment of schizophrenia are also proving useful for bipolar disorder. Hans-Jürgen Möller, M.D Bipolar Disorder and Schizophrenia: Distinct Illnesses or a Continuum? (J Clin Psychiatry 2003;64[suppl 6]:23–27)

Neuroanatomy Ventricular enlargment Prefrontal atrophy Various structural abnormalities have been found in imaging studies of patients with bipolar disorder or schizophrenia, although none has yet provided any clear answers regarding a possible relationship between the 2 disorders. Ventricular enlargment Prefrontal atrophy Disgenesy of hippocampal structure Glycocorticoid hypersecretion Muscle-scheletal anomalies Riduction of number of 5-HT 2 receptors Altered eye movements Cognitive deficits

…nonostante una ampia sovrapposizione delle anomalie strutturali nelle cosiddette psicosi endogene, la corteccia associativa, il sistema limbico e le strutture asimmetriche sono maggiormente coinvolte nella Schizofrenia, mentre lievi anomalie strutturali nei nuclei della base, specie nel nucleo accumbens e nell’area ipotalamica, potrebbero avere un ruolo cruciale nei Disturbi dell’Umore. Baumann, 1999

La diagnosi di schizofrenia basata solo sui sintomi è spesso erronea. Pope & Lipinsky, 1978

Sebbene gli aspetti sintomatologici della schizofrenia si collochino in primo piano rispetto ad altre manifestazioni nell'esame del quadro clinico globale, non emergono, alla luce dei più recenti contributi, sintomi patognomonici o combinazioni di sintomi in grado di differenziare la malattia da altre patologie di confine. (Clayton, 1986)

I confini della schizofrenia e dei disturbi bipolari 'I sintomi della mania o degli stati misti sono spesso simili a quelli della schizofrenia; si tratta di un'ampia zona di confine in cui la diagnosi diviene incerta...' Cassano & Mauri, 1990

Sintomi Psicotici nella Mania • Deliri Grandiosità Riferimento Persecuzione Somatici Nichilistici Bizzarri Sistematizzati • Allucinazioni Uditive Visive Olfattive Tattili • Disturbi formali del pensiero • Sintomi di primo rango • Catatonia (McElroy, 1995)

Episodi maniacali e sintomi psicotici 50% con almeno un delirio 15% con almeno una allucinazione 20% con disturbi formali del pensiero Goodwin and Jamison, 1990

Altrettanto erronea può essere la diagnosi fondata sull'epoca, sulla modalità di esordio, sull'evoluzione sugli esiti.

Number of Psychotic Symptoms as a function of Age at onset in Bipolar Patients 100 80 60 40 20 >3 psychotic symptoms 1-2 psychotic symptoms No psychotic symptoms =/>40 <20 20-29 30-39 Age at onset of Bipolar Illness Rosen et al., 1993

Atypical and subthreshold forms of bipolarity in relation to age at onset Ebephrenia like mania Abrupt & temporary psychomotor agitation Pseudo-conduct disorder mania Early Onset (in childhood & adolescence) Mild elation Marked exhaustibility of the manifestations Partial symptomatology Prevalence of dysphoria over euphoria Paranoid content Late Onset (in elderly)

Enduring deficit syndrome Le modificazioni di personalità, il decorso subcronico, la patologia intercritica persistente, il decadimento della performance sociale, rappresentano aspetti comuni a disturbi mentali diversi. Pertanto anche la specificità del criterio centrato sulla sindrome deficitaria persistente, è in discussione.

Patologia affettiva e Schizofrenia …la patologia affettiva è esclusa dalla schizofrenia sulla base di un arbitrario approccio gerarchico; gli aspetti di decorso e di durata sono stabiliti in modo del tutto convenzionale. CARSON, 1984

Settanta anni dopo Bleuler siamo ancora incapaci di affermare con sicurezza che la schizofrenia rappresenta un'entità unitaria, o più precisamente che i comportamenti convenzionalmente associati con questo termine derivano da un unico nucleo o deficit. Carson, 1984

Rapporti tra diagnosi e trattamento L’ impiego di una categoria diagnostica è in rapporto alla disponibilità di trattamenti efficaci. L’area di un disturbo mentale tende pertanto ad espandersi o a ridursi.

Due aspetti sindromici dello stesso disturbo? Due disturbi distinti ? Due aspetti sindromici dello stesso disturbo?

On a clinical level the overlap between the sindromes of schizophrenia and affective disorders are too broad to be captured by the intermediate diagnosis of schizoaffective disorders. Acta Psychiatr Scand 2006: 13:369-371. Editorial

In contrast to its clinical popularity, research investigations in this diagnostic category -although operational definitions became available - remained relatively rare as it becomes from a PubMed search (search terms in titles: schizoaffective disorder =230 citations; schizophrenia =13.297; bipolar disorder =2.355; during a 10-year period 1995-2005). Acta Psychiatr Scand 2006: 13:369-371. Editorial

The diagnosis ‘schizoaffective disorder’ has not yet been unequivocally defined after more than 70 years. Acta Psychiatr Scand 2006: 13:369-371. Editorial

It is more appropriate to integrate categorical diagnostic concepts with dimensions: a psychotic, a manic and a depressive one, which allows graduations and overlaps. Acta Psychiatr Scand 2006: 13:369-371. Editorial

Treatment of schizoaffective disorders Condition Treatment Acute Episodes Mainly affective episodes Schizomanic (-bipolar) Li, antipsychotics (when highly excited) Schizodepressive Antidepressants, Antipsychotics (Olz, Ris, Zip.) Mainly schizophrenic Schizomanic Antipsychotics Antipsychotics, ECT Long-Term Treatment Mainly affective Schizobipolar Li, Carbamazepine Carbamazepine, Li Antipsychotics (Olz) Maj M, Perris C. Patterns of course in patients with a cross-sectional diagnosis of schizoaffective disorder. J Affect Disord. 1990 Oct;20(2):71-7.

Treatment of schizoaffective disorders: Acute Episodes For mainly affective schizomanic episodes lithium and antipsychotics are the best evaluated medications and should be the first line treatment. In highly excited schizomanic syndromes antipsychotics are superior to lithium. In mainly schizophrenic schizomania antipsychotics are probably the best choice, although there are only few data.

Treatment of schizoaffective disorders: Acute Episodes A difficult to treat condition is the schizodepressed syndrome. Predominantly affective schizodepressed episodes might benefit from treatment with antidepressant or antipsychotics. Olanzapine, risperidone and ziprasidone promising results with regards to schizodepression have to be viewed as preliminary with regard to schizoaffective disorder. Electroconvulsive therapy has not been sufficiently studied in this sub-group. However, given its efficacy in major depression and in schizophrenia it might be a promising treatment option.

Treatment of schizoaffective disorders: long-term treatment First choice for predominantly affective schizobipolar patients is lithium. Carbamazepine was as effective as lithium in one RCT but is less well studied. From one RCT, however, it appears that carbamazepine might be superior to lithium in the sub-group of mainly affective schizodepressive patients. A family history of bipolar disorder and pronounced suicidality also supports lithium. This, however, is an analogy to bipolar disorder and has not been shown for SAD. In pts with mainly schizophrenic SAD antipsychotics are the long-term treatment of choice and, in the absence of sufficient data, treatment decision have to be made in analogy to schizphrenia.

Treatment of schizoaffective disorders: long-term treatment For SAD, olanzapine is the only drug has been tested in a RCT in long-term treatment. From observational studies there are encouraging results for the use of clozapine in SAD long-term treatment. Combination treatment is increasingly common (1). However, it has not been well studied (2). For SAD, therefore, combination should be deployed only after monoterapy fails. Combination of lithium and haloperidol(3) as well as lithium and carbamazepine(4) have been reported to be safe and affective. Kupfer et al. Demographic and clinical characteristics of individuals in a bipolar disorder case registry. J Clin Psychiatry. 2002 Nov;63(11):1045-6 Baethge C et al. Long-term combination therapy versus monotherapy with lithium and carbamazepine in 46 bipolar I patients.J Clin Psychiatry. 2005 Feb;66(2):174-82 Lowe MR and Batchelor DH. Lithium and neuroleptics in the management of manic depressive psychosisHuman psychopharmacology, 5, 267-74 Bocchetta A.Carbamazepine augmentation in lithium-refractory bipolar patients: a prospective study on long-term prophlyactic effectiveness. Clin Psychopharmacol. 1997 Apr;17(2):92-6.

Conclusion … ‘patients with schizoaffective disorders in their majority have in fact a different social adaption, a different symptomatology, and a different prognosis than pure schizophrenic patients. It is useful for the physician and it is a hope for the patient to know that. A useful clinical diagnosis which concerns millions of people can not be abandoned in favour of permanently changing theoretical concepts’. A. Marneros: Letters to the Editor. Acta Psychiatr Scand 2007: 115: 162–165