Treating Depression in Schizophrenia

Presented at the 2011 NEI Global Psychopharmacology Congress.

an der Heiden, W. et al. (2005) Depression in the long-term course of schizophrenia. Eur Arch Psychiatry Clin Neurosci 255 (3), 174-184.

Barnes, T.R. (2011) Evidence-based guidelines for the pharmacological treatment of schizophrenia: recommendations from the British Association for Psychopharmacology. J Psychopharmacol 25 (5), 567-620.

Buchanan, R.W. et al. (2010) The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements.Schizophr Bull 36 (1), 71-93.

Canuso, C.M. et al. (2010) Efficacy and safety of paliperidone extended-release in schizophrenia patients with prominent affective symptoms. J Affect Disord 120 (1-3), 193-199.

Clay, H.B. et al. (2011) Mitochondrial dysfunction and pathology in bipolar disorder and schizophrenia. Int J Dev Neurosci 29 (3), 311-324.

Conley, R.R. et al. (2007) The burden of depressive symptoms in the long-term treatment of patients with schizophrenia. Schizophr Res 90 (1-3), 186-197.

Corcoran, C.M. et al. (2011) The relationship of social function to depressive and negative symptoms in individuals at clinical high risk for psychosis. Psychol Med 41 (2), 251-261.

Correll, C.U. (2010) Understanding schizoaffective disorder: from psychobiology to psychosocial functioning. J Clin Psychiatry 71 Suppl 2, 8-13.

Dussias, P. et al. (2010) Polypharmacy of schizophrenia. Psychiatry (Edgmont) 7 (8), 17-19.

Felmet, K. et al. (2011) Elderly patients with schizophrenia and depression: diagnosis and treatment. Clin Schizophr Relat Psychoses 4 (4), 239-250.

Hawton, K. et al. (2005) Schizophrenia and suicide: systematic review of risk factors. Br J Psychiatry 187, 9-20.

Kantrowitz, J.T. and Citrome, L. (2011) Schizoaffective disorder: a review of current research themes and pharmacological management. CNS Drugs 25 (4), 317-331.

Kasckow, J. et al. (2010) Treatment of subsyndromal depressive symptoms in middle-aged and older adults with schizophrenia: effect on functioning. Int J Geriatr Psychiatry 25 (2), 183-190.

Kollias, C.T. et al. (2008) Association of physical and social anhedonia with depression in the acute phase of schizophrenia. Psychopathology 41 (6), 365-370.

Stahl, S. (2008) Psychosis and Schizophrenia. In Stahl's Essential Psychopharmacology, Cambridge University Press.

Treatment of schizophrenia 1999. The expert consensus guideline series. J Clin Psychiatry 60 Suppl 11, 3-80.

van Winkel, R. et al. (2008) Evidence that the COMTVal158Met polymorphism moderates subclinical psychotic and affective symptoms in unaffected first-degree relatives of patients with schizophrenia. EurPsychiatry 23 (3), 219-222.

Prevalence and Consequences of Depressive Symptoms in Schizophrenia

Affective symptoms are common in schizophrenia; depressive symptoms are reportedin as many as 80% of patients with schizophrenia while symptoms of mania arereported in as many as 20% of individuals with schizophrenia. In addition to those whomeet criteria for major depression, there are also a significant number of patients withschizophrenia who experience subsyndromal depressive symptoms. Depressivesymptoms in patients with schizophrenia can have devastating consequences includingincreased risk of psychotic relapse and hospitalization, worse social functioning, andpoorer quality of life compared with patients with schizophrenia who do not haveprominent affective symptoms. Depressive symptoms significantly increase the risk ofsuicide; the majority (64%) of patients with schizophrenia who commit suicide do sowhile experiencing depressive symptoms. Similarly, suicide attempts are even morecommon in individuals with schizoaffective disorder compared to those with eitherschizophrenia or a mood disorder. Interestingly, suicide risk has not been associatedwith either positive or negative symptom domains.

Treatment of Depressive Symptoms with Atypical AntipsychoticsThere are no consistent recommendations as to how schizoaffective disorder or depressive symptoms in schizophrenia are most effectively treated. Despite thisfact, antidepressants and/or mood stabilizers are often used in conjunction with antipsychotics for the treatment of schizophrenia. The 1999 Expert ConsensusGuidelines recommend treatment of schizophrenia and comorbid depression first with optimal doses of SGAs, followed by augmentation with an SSRI, followedby the serotonin and norepinephrine reuptake inhibitor (SNRI) venlafaxine, and finally, bupropion. More recent guidelines have indicated that there are notenough data on which to base a recommendation for the treatment of depressive symptoms in schizophrenia.

AntipsychoticsAlthough FGAs may exacerbate affective symptoms in schizophrenia by causing hypodopaminergia in the cortex (Fig. 2C), all SGA's, via antagonism atserotonin 5HT2A receptors, and many SGAs via antagonism at 5HT2C receptors, may reduce negative, affective, and cognitive symptoms (Fig. 2D) byincreasing dopamine activity in the same brain region. Additional binding properties of some SGA's that lead to increased dopamine, norepinephrine, andserotonin activity in the cortex, such as norepinephrine reuptake blockade, alpha 2 adrenergic antagonism, 5HT1A partial agonism, 5HT7 antagonism and otherproperties, may also lend these agents antidepressant properties.

It has been hypothesized that, in depression, dopamine neurotransmission is reduced, resulting in deficient tonic activity at dopamine D3 receptors and deficientphasic activity at dopamine D2 receptors. Partial agonism of D2/D3 receptors may reset the tonic and phasic dopamine neurotransmission, resulting inantidepressant effects. Aripiprazole, an SGA with D2/D3 partial agonist activity, has been shown to improve depression. Additionally, the actions of D2/D3 partialagonists may have antipsychotic and antimanic effects due to net antagonist activity at overstimulated D2/D3 receptors.

Enhancement of noradrenergic neurotransmission in the PFC, via norepinephrine reuptake inhibition (NRI) is another proposed mechanism for antidepressantactivities of antipsychotics. Both ziprasidone and quetiapine (via its active metabolite norquetiapine) may exert antidepressant effects in part through thismechanism of enhanced norepinephrine neurotransmission. Ziprasidone has the additional property of serotonin reuptake inhibition (SRI) which may alsocontribute antidepressant effects by increasing serotonergic neurotransmission.

Antagonism at serotonin 5HT2C receptors, a property shared by many SGAs, may also have an antidepressant effect through disinhibition of dopamine andnorepinephrine release in the prefrontal cortex (PFC). SGAs with 5HT2C antagonistic activities include olanzapine, ziprasidone, and quetiapine.

Similar to antagonism of 5HT2C receptors, agonism of serotonin 5HT1A receptors leads to disinhibition of noradrenergic and dopaminergic neurons in the PFCand 5HT1A agonism has been shown to increase serotonin, dopamine, and norepinephrine neurotransmission. There are many SGAs that bind to 5HT1Areceptors and may therefore have some antidepressant capacity.

Blockade of serotonin 5HT7 receptors may have antidepressant effects by increasing serotonergic neurotransmission in the PFC; antagonism of 5HT7 receptorsin the raphe nuclei leads to disinhibition of serotonergic neurons. Several SGAs have binding affinity for 5HT7 receptors, including lurasidone, asenapine, andaripiprazole.

Adrenergic alpha-2 receptors are found on cell bodies of noradrenergic neurons. Antagonism of alpha-2 receptors is postulated to have antidepressant effectsby increasing norepinephrine neurotransmission. There are several SGAs that may have antidepressant properties due to antagonism of alpha-2 receptors,including asenapine, paliperidone and risperidone.

Suicide is of great concern for patients with schizophrenia, especially those in whom affective symptoms are present. Clozapine has been found to reduce risk ofsuicide and is now recommended for patients exhibiting suicidal tendencies or ideation. However, caution should be exercised when using clozapine due toincreased risk for serious side effects, including agranulocytosis.

Paliperidone was recently approved for the treatment of schizoaffective disorder. Paliperidone may derive its mood stabilizing effects from serotonin 5HT2A,5HT2C, or 5HT7 antagonism, adrenergic alpha-2 antagonism, and/or binding affinity for dopamine D3 receptors.

Schizoaffective DisorderDepressive symptoms in schizophrenia can present as schizoaffective disorder,comorbid depression, or as subsyndromal depression in which depressive symptomsdo not meet criteria for major depression. Schizoaffective disorder is described asschizophrenia in which the patient also meets criteria for a mood disorder (majordepressive episode, manic episode, or mixed episode). The diagnostic criteria forschizoaffective disorder also require that psychotic symptoms are present withoutprominent mood symptoms for at least 2 weeks.

Comorbid and Subsyndromal DepressionComorbid and subsyndromal depression can occur before, during, or after a psychoticepisode. In fact, depressive symptoms can be a sign of imminent psychotic relapse inmany patients. Affective symptoms are among the most prevalent prodromal signs withas many as 83% of patients suffering a depressed mood in the weeks leading up to afirst hospitalization for psychosis. In patients at risk for developing schizophrenia,symptoms of depression and anxiety may predict higher risk for subsequentdevelopment of psychosis and higher severity of first-episode psychosis. In this context,symptoms of depression and anxiety may serve as vulnerability markers in individualsat risk for developing schizophrenia. Depressive symptoms that occur during apsychotic episode are often amenable to treatment. Post-psychotic depression,occurring after a psychotic episode, may persist and worsen in some individuals andoften is associated with a poor prognosis.

The Neurobiology of Depression in Schizophrenia

Ultimately, the expression of symptoms is largely due to dysfunctioning ofneurotransmitter systems (Fig. 1). It may be that the disruption of one system (e.g.dopamine) underlying schizophrenia has downstream effects that lead to misregulationof other neurotransmitter systems (e.g. serotonin) that underlie the expression ofaffective symptom. Alternatively, there may be a common genetically predisposingfactor (e.g. catechol-o-methyltransferase; COMT) or process (e.g. energy metabolism)that leads to dysfunction of multiple systems simultaneously.

Treatment with medications that block dopamine D2 receptors (i.e. antipsychotics) mayinduce affective and negative symptoms by exacerbating a hypodopaminergic status inthe ventromedial prefrontal cortex (VMPFC). Additional blockade of serotonin 5HT2Areceptors by atypical, second-generation antipsychotics (SGAs) is hypothesized tomitigate affective, negative, and cognitive symptoms caused by excessive D2antagonism in the cortex (Fig. 2).

Figure 1. Disrupted Circuits in Schizophrenia and DepressionDysfunction in various neurotransmitter systems are hypothesized to underlie the symptoms of schizophrenia. A) The dopamine hypothesis of schizophrenia proposes that hyperdopaminergia in the limbic system underlies the positive symptoms of schizophrenia. B) Negative and cognitive symptoms in schizophrenia are believed to be due to hypodopaminergia in the dorsolateral prefrontal cortex (DLPFC) whereas hypodopaminergia in the ventromedial prefrontal cortex may contribute to the negative and affective symptoms of schizophrenia. C) The monoamine hypothesis of depression proposes that depressive symptoms may be due to a deficiency of norepinephrine (NE), dopamine (DA), and/or serotonin (5HT) neurotransmission in the prefrontal cortex.

Figure 2. Antipsychotics and Affective SymptomsA) Unlike conventional antipsychotics (which bind primarily to dopamine D2 receptors, atypical antipsychotics also bind to serotonin 5HT2A receptors. B) In the mesocortical pathway, binding of serotonin to 5HT2A receptors causes a state of hypodopamine. C) Conventional antipsychotics exacerbate hypodopaminergia in the cortex and may cause secondary affective, negative, and cognitive symptoms. D) Additional antagonism of serotonin 5HT2A receptors by atypical antipsychotics may help ameliorate some of the symptoms caused by hypodopaminergia in the cortex.

A. The Mesolimbic Dopamine Hypothesis of Positive Symptoms of Schizophrenia

mesolimbic overactivity

positive symptoms

overreactionnormalbaselinehypoactivation

LOW

normal

B. Mesocortical Pathway to DLPFC and VMPFC

VMPFC

DLPFC

affective symptoms

(SIGH)

negativesymptoms

(SIGH)

negativesymptoms

cognitive symptoms

DA

C. Monoamine Hypothesis of Depression

NE

5HT

D2

5HT2A

A

DA neuron

postsynapticneuron

DA

5HT neuron

5HT2A receptor

stimulate5HT2A receptor

D2 receptorno DA release

DA neuron

postsynapticneuron

5HT neuron

B

DA neuron

5HT neuron

D

affective symptoms

(SIGH)

negativesymptoms

cognitive symptoms

DA neuron

5HT neuron

C

affective symptoms

(SIGH)

negativesymptoms

cognitive symptoms