The hodgepodge of psychosis comorbidities has long been considered as unsurprising consequences of psychosis itself. But what if it were the other way around? In most cases, comorbidities actually precede psychosis onset, then transform into psychotic symptoms. Just maybe, these overlooked comorbidities actually define clinical subtypes that finally dissect schizophrenia into definable, symptomatically distinct, and treatable subtypes.
One published evolutionary theory1 posits five core anxiety and depressive subtypes, each one evolved from a primeval social instinct: (1) social anxiety (social ranking to reduce competitive strife), (2) panic anxiety (separation anxiety for group cohesion and safety), (3) obsessive-compulsive disorders (behaviors for healthy, wealthy, and wise groups), (4) atypical depression (rejection sensitivity for inoffensiveness, and thus social harmony), and (5) melancholic depression (fatal illness or severe loss lead to death, thus preserving group resources).
Known psychoto-genesis theories may help explain comorbidity-generated psychoses: heightened dopaminergic activity leads to intensification of instinct imperative, whereas prefrontal cortex hypo-frontality leads to reduced conscious modulation of instincts. There may be five proposed psychosis comorbidity subtypes: (1) psychotic depression (melancholic depression), (2) delusional disorder (social anxiety), (3) mania (atypical depression), (4) schizo-obsessive disorder, and (5) panic psychosis (panic anxiety).1
Each of these comorbidities' associated subtypes is supported by modest to significant research, with psychotic melancholia widely accepted. Research already suggests that these five subtypes may account for most functional psychosis. This article focuses on a proposed “panic psychosis” that looks clinically like paranoid schizophrenia with voices.2,3 It revisits, updates, and expands on a discussion from the year 2000.4 As with the other comorbidity subtypes, supporting evidence includes near-psychotic features of nonpsychotic panic anxiety,5 phenomenological similarities of the nonpsychotic/psychotic versions, appearance of the nonpsychotic diagnosis within the corresponding psychosis, enhanced psychosis response with comorbidity pharmacotherapy, and emerging genetic and neurochemical findings. Importantly, there are significant barriers to comorbidity diagnosis in patients who have psychosis, but also new tools for research and clinical diagnoses.6–8
Because schizophrenia wreaks such devastation on social and occupational function, cognition and reality testing, searching for seemingly trivial panic anxiety is essential. Indeed, comorbid panic anxiety may be a major determinant of distress and dysfunction across many other psychiatric disorders.9,10 Diagnostic recognition of panic in schizophrenia is crucial for effective treatment. For comparison, the discovery of lithium made the distinction between psychotic mania and schizophrenia far more clinically pressing. This article is based on controlled research and clinical observation.
Panic Anxiety and Schizophrenia Comorbidity
Many studies have examined panic prevalence in schizophrenia, with prevalence ranging from 16% to 100%.8,11 This wide variation has many causes. First, panic prevalence may differ among schizophrenia subtypes; panic is far more frequent with auditory hallucinations, more severe symptoms, or paranoid schizophrenia.8,12,13 Second, schizophrenic severity and subtyping approaches may vary. Third, different sites may vary in patient participation and symptom articulation. One study showed that patients with schizophrenia with greater cognitive impairment were less likely to report panic history.6 Importantly, diagnostic tools differ greatly in sensitivity and specificity (eg, SCID [Structured Clinical Interview for DSM] vs SCID-UP [Upjohn Version], and SADS [Schedule for Affective Disorders and Schizophrenia] vs SADS-LA [Lifetime Anxiety] showed that a more refined approach to panic diagnosis lead to more sensitive data).
None of these instruments is a substitute for a skillful interview, however, especially when attuned to the confusing concurrence of panic symptoms with psychotic exacerbation. So, assessment sensitivity may significantly influence prevalence numbers. Lastly, interviewers must remember that panic anxiety is usually an internally experienced event that is generally not even evident to a trained observer. Even nonpsychotic panic anxiety is not usually evident to patients until diagnosed.
One structured approach (Panic and Schizophrenia Interview [PaSI]) yielded panic rates of 100% and 73% in two small studies of paranoid schizophrenia with voices.7,8 The PaSI focuses the patient's attention on the instant of paroxysmal onset voices, and then repeatedly refocuses on that moment while inquiring about each of the panic anxiety symptoms in the DSM-514 diagnostic criteria. In two small studies, PaSI results matched clinical diagnosis, and in one of those, PaSI reults matched CO2 panic challenge test results.
Even more compelling are studies using the diagnostic carbon dioxide challenge test for panic anxiety in schizophrenia. One patient with schizophrenia but no apparent panic anxiety underwent a 35% CO2/65% O2 inhalation challenge test for panic (J. P. Kahn, unpublished data, 1988).15 Panic and voices ensued, along with newly recalled prodromal panics, and panic anxiety symptoms concurrent with previous voices. Adjunctive alprazolam produced marked clinical improvement. A later study of paranoid schizophrenia with voices found CO2-induced panic anxiety in all eight participants.8
Beyond comorbidity prevalence, other research suggests familial aggregation of panic anxiety and schizophrenia,16 supporting a genetic connection between the two syndromes. Studies of gamma-aminobutyric acid (GABA) (the neurotransmitter that reduces various forms of anxiety) also suggest a connection between schizophrenia and panic. For example, first-degree relatives of patients with schizophrenia have a distinct GABA response to single-dose alprazolam.17 And, reduced GABA activity in the prefrontal cortex is associated with impaired sociability, suggestive of the negative symptom social withdrawal in schizophrenia.18
Similarly, oxytocin activity levels may play an important role in the shift from excitatory to inhibitory neurotransmission of GABA, which occurs immediately before birth and during brain maturation.19,20 So, because the oxytocin receptor genetic variant may lead to interruptions in oxytocin signaling, it may thus contribute to psychiatric vulnerability (through neurotrophin-mediated pathways for neurodevelopment and neuroplasticity, particularly in conjunction with environmental stressors).21
Clinical Observations on Natural History
Clinical observation experience in varied schizophrenia clinical population settings suggests that comorbid panic anxiety prevalence is closer to the higher estimates, especially in patients with panic psychosis. Moreover, patients often retrospectively report panic anxiety as part of their prepsychotic prodrome.22
For example, after a few months or years of panic attacks, panic begins to include new symptoms of confusion, fearfulness, or paranoia. Soon after, abrupt panic anxiety becomes paroxysmally concurrent with auditory hallucinations. So, even though panic anxiety symptoms continue, they are masked by the psychotic concurrence of voices. Critical and threatening voices insistently demand attention, as they primevally warn of imminent dangers. From the evolutionary perspective, this may be a more primal form of the separation anxiety central to panic.1 Perhaps if you are emotionally trapped or far from home, then the voices warn that there may be predators about.
Clinical experience and existing data suggest that panic psychosis typically looks like classic paranoid schizophrenia with voices. Psychotic symptoms related to other comorbid diagnoses such as obsessive-compulsive disorder and social anxiety can occur in the same patients. Antipsychotic medication can reduce or sometimes eliminate psychotic symptoms. But, negative symptoms of social and emotional withdrawal typically persist. ln many patients, social withdrawal may be a psychotic analog of agoraphobia. For example, if paranoia prevents leaving the house, antipsychotics might relieve psychosis but not reclusiveness. Panic anxiety and agoraphobia, now absent psychotic features, may become more apparent.4 In addition, ongoing paranoid thoughts may be a psychotic analog of the anticipatory anxiety of panic disorder.
Diagnosing Panic in Schizophrenia
To make the diagnosis of panic anxiety, clinicians must possess specific interviewing skills, and must actively interview for possible panic anxiety symptoms.5 Among patients who are actively experiencing psychosis, this interview process may begin with questions about those psychotic phenomena potentially related to panic symptoms.4 For example, most patients have auditory hallucinations that come and go. First, ask them to focus on the temporal onset pattern of voices. Is there paroxysmal onset, increase, or qualitative change? Then, with repeated reminders to focus on that paroxysmal moment, ask whether it coincides with onset or increase of anxiety, panic, tachycardia, chest pain, shortness of breath, and the other diagnostic criteria for panic anxiety symptoms. It is important to understand the seemingly commonsense patient perception that panic symptoms must be caused by the voices.
When paroxysmal voices are accompanied by panic symptoms, they might be panic anxiety with voices as an additional and psychotic symptom. Other patients may experience a paroxysmal increase in paranoid fear, which may then be examined similarly.23 For example, another patient with schizophrenia became abruptly afraid that other people were reading her mind and plotting against her.
Importantly, panic disorder is a chronic syndrome, and usually begins well before first-psychosis onset.24 Nonpsychotic panics may also occur when psychosis remits on antipsychotic medication.25 Patient history of prepsychotic and nonpsychotic episodes can be found through careful standard questions about standard diagnostic criteria for panic symptoms, as well as by screening for phobias and associated panic.4 Just like patients who are nonpsychotic with panic, patients with schizophrenia during nonpsychotic periods can have panic symptoms that are mistakenly labeled as medical diagnoses or mere physical complaints (eg, noncardiac chest pain, dizziness, asthma, and seizures). Because nonpsychotic panic anxiety may seem mild or ordinary to the patient, careful inquiry is required.4 The diagnosis and chronology of panic and psychosis are often easier to determine after antipsychotic response.24
Adjunctive Clonazepam and Alprazolam
In these studies, unselected patients with schizophrenia have been treated with adjunctive alprazolam.26,27 Some patients experienced significant reductions in positive and negative symptoms, whereas other patients did not benefit. But adjunctive alprazolam produces a broadly beneficial effect for patients with comorbid panic and schizophrenia,2,3 suggesting that panic anxiety is not only a significant marker for the response to alprazolam (and clonazepam) in schizophrenia, but may also be a pathogenetic contributor. Notably, those benzodiazepines that lack a significant antipanic effect do not benefit schizophrenia in this way.
Combined antipsychotic and antipanic medication appear to be the most beneficial approach. Although no specific antipsychotic appears to be more effective for patients who have comorbid panic and schizophrenia, newer atypical antipsychotics may be better tolerated.4 Although anecdotal reports suggest that antipsychotics worsen panic in some patients,25 this may be just the emergence of nonpsychotic panic anxiety on relief of psychosis.
Of the many antipanic medications currently in use, only clonazepam and alprazolam seemingly have clear and substantial benefit for positive and negative symptoms of schizophrenia as well as panic anxiety, and are the only benzodiazepines approved by the US Food and Drug Administration (FDA) for nonpsychotic panic.28 Clonazepam is typically preferred because of its longer half-life and lower potential for abuse.
Antipanic tricyclic antidepressants and selective serotonin reuptake inhibitors offer little benefit for positive and negative schizophrenia symptoms.22,23 Research supports the adjunctive use of other benzodiazepine medications in the treatment of schizophrenia.26,29,30 However, these other medications have limited benefit for positive or negative symptoms or for panic.
Neither clonazepam nor alprazolam are established nor FDA-approved for schizophrenia or psychosis; however, clonazepam may be started concurrently with antipsychotics when indicated by the presence of panic, anxiety, or voices that include panic. For example, during inpatient treatment, clonazepam might be started at a fixed dose of 0.5 mg every 12 hours (without as needed dosing), and then gradually increased to complete cessation of all panic anxiety symptoms (including voices with panic).4
On close observation, some initial clinical improvement might be seen hours after a first dose, although 2 days may pass before the full benefit of a given clonazepam dose appears. As with panic alone, fully effective doses range from 2 to 5 mg/day in total, equally divided into an every 8-hour or every 12-hour fixed dose. This dose range is similar to that for nonpsychotic panic anxiety, where complete response typically requires between 2 and 4 mg/day in total.30
Addition of clonazepam has several benefits: prompt reduction of anxiety (and further anxiety reduction after panic cessation), phobia reduction, increased social interaction, increased affective relatedness, and improved cognition. These benefits may be accompanied by other negative symptom reduction.3 Positive symptoms including auditory hallucinations may improve rapidly, whereas paranoid delusions gradually begin to fade in importance. Significant functional improvement occurs much more slowly. Overall, shorter illness duration predicts faster and better clinical response. ln patients with robust response to antipanic medication, the dosage requirements for antipsychotics may eventually decrease, whereas clonazepam benefits apparently persist with stable dosage over time.
Clonazepam may cause some mild drowsiness at the onset, and with each dosage increase. Although it typically diminishes over several days, patients often complain of tiredness (up to 37%, according to the FDA).31 This is most important for patients who drive, use machinery, or take other sedating medications. Clonazepam may cause or contribute to gait disturbances and falls, especially in patients with central nervous system damage. Clonazepam, like all benzodiazepines, may cause physical dependency with consequent risk of withdrawal symptoms on abrupt cessation. However, because it does not produce a high, it has a lower potential for abuse, even among patients who abuse drugs or alcohol. Nevertheless, caution is warranted when prescribing clonazepam to patients who abuse substances.4 Clonazepam for panic treatment does not lead to antipanic tolerance or escalating dosages.
Positive response to medication may cause patients with panic and schizophrenia to become noncompliant. Despite their recognition of symptom relief, the reduction of symptoms can be confusing and distressing, especially among patients with chronic psychosis. So, after some weeks, their complaints of side effects and drowsiness increase even if appearing alert. Actual sedative effects are likely to have diminished by then.
Clinicians can acknowledge side effects as well as the life changes and explore ways to help the patient adapt. Because outpatients are more difficult to monitor than inpatients, lower initial clonazepam doses and more gradual increases can diminish this noncompliance. And, as clinical improvement progresses, there is an opportunity to look again for such other comorbidities as obsessive-compulsive disorder, social phobia, and atypical depression.
Psychotherapy of Treatment Response, and Beyond
Skilled psychotherapy is essential to address the treatment of severe and long-term symptoms, the growth of new opportunities, and their entanglement with similar emotional conflict that affect most patients with schizophrenia and their entanglement with the same kinds of emotional conflict that affect nearly everyone.4 Absence of proper support and psychotherapy increases the likelihood of noncompliance. In some patients, increasingly supportive psychotherapy can eventually lead to effective psychodynamic work and progress.
Summary and Looking Ahead
Panic and schizophrenia often occur comorbidly as panic psychosis, with substantial treatment implications.4 An antipsychotic combined with an every 12-hour fixed dose of clonazepam will often result in marked improvement of panic symptoms, and both the positive and negative symptoms of schizophrenia.2 A major impediment to ongoing benefit is the psychological response to symptom reduction, unless diminished with psychotherapy.
The premorbid occurrence of panic anxiety, concurrence of panic anxiety with psychotic exacerbations, and the global response to antipanic treatment all suggest that panic may have a pathophysiologic relationship to some schizophrenia.
So, it might well be that there are five psychosis subtypes, and that some schizophrenia is actually a panic psychosis. To find out, we need first-rate research on accurate diagnosis and diagnostic methods, as well as on clonazepam and other possibly effective treatments. And it wouldn't hurt to further explore the clinical phenomenology, natural history, underlying pathophysiology, neurochemistry, and genetics.
- Kahn JP. Angst: Origins of Anxiety and Depression. Oxford, United Kingdom: Oxford University Press; 2012.
- Kahn JP, Puertollano MA, Schane MD, Klein DF. Schizophrenia, panic anxiety, and alprazolam. Am J Psychiatry. 1987;144:527–528. doi:10.1176/ajp.144.4.527b [CrossRef]
- Kahn JP, Puertollano MA, Schane MD, Klein DF. Adjunctive alprazolam for schizophrenia with panic anxiety: observation and pathogenetic implications. Am J Psychiatry. 1988;145:742–744. doi:. doi:10.1176/ajp.145.6.742 [CrossRef]
- Kahn JP, Meyers JR. Treatment of comorbid panic disorder and schizophrenia: evidence for a panic psychosis. Psychiatr Ann. 2000; 30(1):29–33. doi:. doi:10.3928/0048-5713-20000101-08 [CrossRef]
- Masdrakis VG, Legaki EM, Papageorgiou C, Markianos M. Psychoticism in patients with panic disorder with or without comorbid agoraphobia. Int J Psychiatry Clin Pract. 2017;21:181–187. doi:. doi:10.1080/13651501.2017.1305111 [CrossRef]
- Rapp EK, White-Ajmani L, Antonius D, et al. Schizophrenia comorbid with panic disorder: evidence for distinct cognitive profiles. Psychiatry Res. 2012;197(3):206–211. doi:. doi:10.1016/j.psychres.2012.01.017 [CrossRef]
- Veras AB, Cougo S, Meira F, et al. Schizophrenia dissection by five anxiety and depressive subtype comorbidities: clinical implications and evolutionary perspective. Psychiatry Res. 2017;257:172–178. doi:. doi:10.1016/j.psychres.2017.07.048 [CrossRef]
- Savitz AJ, Kahn TA, McGovern KE, Kahn JP. Carbon dioxide induction of panic anxiety in schizophrenia with auditory hallucinations. Psychiatry Res. 2011;189(1):38–42. doi:. doi:10.1016/j.psychres.2011.06.008 [CrossRef]
- Cutler J. Panic attacks and schizophrenia: assessment and treatment. Psychiatr Ann. 1994;24:473–476. doi:. doi:10.3928/0048-5713-19940901-09 [CrossRef]
- Sandberg SG, Siris SG. Panic disorder in schizophrenia. J Nerv Ment Dis. 1987;175:627–628. doi:10.1097/00005053-198710000-00009 [CrossRef]
- Moorey H, Soni SD. Anxiety symptoms in stable chronic schizophrenics. J Mental Health. 1994;3:257–262. doi:. doi:10.3109/09638239409003807 [CrossRef]
- Labbate LA, Young PC, Arana GW. Panic disorder in schizophrenia. Can J Psychiatry. 1999;44:488–490. doi:. doi:10.1177/070674379904400510 [CrossRef]
- Ulas H, Alptekin K, Akdede BB, et al. Panic symptoms in schizophrenia: comorbidity and clinical correlates. Psychiatry Clin Neurosci. 2007;61(6):678–680. doi:10.1111/j.1440-1819.2007.01724.x [CrossRef]
- American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Publishing; 2013.
- Woods SW, Charney OS, Goodman WK, Heninger GR. Carbon dioxide-induced anxiety. Behavioral, physiologic, and biochemical effects of carbon dioxide in patients with panic disorders and healthy subjects. Arch Gen Psychiatry. 1988;45:43–52. doi:10.1001/archpsyc.1988.01800250051007 [CrossRef]
- Heun R, Maier W. Relation of schizophrenia and panic disorder: evidence from a controlled family study. Am J Med Genet. 1995;60:127–132. doi:. doi:10.1002/ajmg.1320600208 [CrossRef]
- Wolf DH, Satterthwaite TD, Loughead J, et al. Amygdala abnormalities in first-degree relatives of individuals with schizophrenia unmasked by benzodiazepine challenge. Psychopharmacology (Berl). 2011;218(3):503–512. doi:. doi:10.1007/s00213-011-2348-7 [CrossRef]
- Paine TA, Swedlow N, Swetschinski L. Decreasing GABA function within the medial prefrontal cortex or basolateral amygdala decreases sociability. Behav Brain Res. 2017;317:542–552. doi:. doi:10.1016/j.bbr.2016.10.012 [CrossRef]
- Tyzio R., Cossart R., Khalilov I., et al. Maternal oxytocin triggers a transient inhibitory switch in GABA signaling in the fetal brain during delivery. Science. 2006;314:1788–1792. doi:. doi:10.1126/science.1133212 [CrossRef]
- Valeeva G, Valiullina F, Khazipov R. Excitatory actions of GABA in the intact neonatal rodent hippocampus in vitro. Front Cell Neurosci. 2013;7:20. doi:. doi:10.3389/fncel.2013.00020 [CrossRef]
- Veras AB, Getz M, Froemkee RC, et al. Rare missense coding variants in oxytocin receptor (OXTR) in schizophrenia cases are associated with early trauma exposure, cognition and emotional processing. J Psychiatric Res. 2018;97:58–64. doi:. doi:10.1016/j.jpsychires.2017.11.011 [CrossRef]
- Davies N, Russell A, Junes P, Murray RM. Which characteristics of schizophrenia predate psychosis?J Psychiatr Res. 1998;32:121–131. doi:10.1016/S0022-3956(97)00027-7 [CrossRef]
- Galynker I, Ieronimo C, Perez-Acquino A, Lee Y, Winston A. Panic attacks with psychotic features. J Clin Psych. 1996;57:402–406.
- Tien AY, Eaton WW. Psychopathologic precursors and sociodemographic risk factors for the schizophrenia syndrome. Arch Gen Psychiatry. 1992;49:37–46. doi:10.1001/archpsyc.1992.01820010037005 [CrossRef]
- Iruela LM, Ibanez-Rojo V, Oliveros SC, Caballero L. Panic attacks in schizophrenia. Br J Psychiatry. 1991;158:436–437. doi:10.1192/bjp.158.3.436a [CrossRef]
- Wolkowitz OM, Pickar D, Doran AR, Breier A, Tarell J, Paul SM. Combination alprazolam-neuroleptic treatment of the positive and negative symptoms of schizophrenia. Am J Psychiatry. 1986;143:85–87. doi:10.1176/ajp.143.1.85 [CrossRef]
- Csernansky JG, Lombrozo L, Gulevich GD, Hollister LE. Treatment of negative schizophrenic symptoms with alprazolam: a preliminary open-label study. J Clin Psychopharmacol. 1984;4:349–352. doi:10.1097/00004714-198412000-00013 [CrossRef]
- Nardi AE, Cosci F, Balon R, et al. The prescription of benzodiazepines for panic disorder: time for an evidence-based educational approach. J Clin Psychopharmacol. 2018;38(4):283–285. doi:. doi:10.1097/JCP.0000000000000908 [CrossRef]
- Wolkowitz OM, Turetsky N, Reus VI, Hargreaves WA. Benzodiazepine augmentation of neuroleptics in treatment-resistant schizophrenia. Psychopharmacol Bull. 1992;28:291–295.
- Nardi AE, Machado S, Almada LF, et al. Clonazepam for the treatment of panic disorder. Curr Drug Targets. 2013;14(3):353–364.
- Klonopin tablets (clonazepam). https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/017533s053,020813s009lbl.pdf. Accessed November 26, 2018.