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Panksepp 2011 Why Does Depression Hurt Diminished Brain Reward

Panksepp 2011 Why Does Depression Hurt Diminished Brain Reward

Psychiatry 74(1) Spring 2011 5

Why Does Hurt? Panksepp and Watt

Why Does Depression Hurt? Ancestral Primary- Process Separation-Distress (/) and Diminished Brain Reward (SEEKING) Processes in the Genesis of Depressive Jaak Panksepp and Douglas Watt

What can affective add to ry-process nature). Although every aspect of the discussion of the genesis of depression? the affective life can be influenced by depres- Among other contributions, it may begin to sion, depression is intimately related to 1) answer the question of why depression feels sustained overactivity of the separation-dis- so bad. Since it is the only basic neuroscience tress PANIC system that can, if prolonged, approach that specifically aims to take the lead to a downward cascade of psychological affective infrastructure of the evolved mind despair (a theoretical view originally formu- as its central focus, it offers testable hypoth- lated by John Bowlby); and 2) the despair eses concerning the affective imbalances that phase that follows the acute PANIC response contribute to clinical depression (Solms & which is characterized by abnormally low Panksepp, 2011). A critical question about activity of the SEEKING system. In terms genesis of depression is: Which negative of animal modeling, depression reflects the affect-generating networks of mammalian behavioral agitation of separation distress brains are most important for followed by emotional shutdown. The initial depressive “” and what new therapeu- behaviorially agitated panic state may include tics might such knowledge engender? SEEKING , followed by dramatically has outlined diminished SEEKING during the depressive seven primary process (i.e., genetically pro- “despair phase.” From this perspective, de- vided) emotional systems. All are subcorti- pression may have evolutionary advantages, cally situated (Panksepp, 1998), where ani- such as conservation of resources follow- mal models allow causal (vs. correlational) ing unalleviated separation distress. A more analysis, not afforded by research, detailed exposition of this view, along with including modern brain imaging. These pri- seven expert commentaries, is available in mary functions consist of SEEKING, , Watt and Panksepp (2009). Here, we briefly , sexual , maternal CARE, sepa- summarize the implications of this perspec- ration-distress PANIC/GRIEF (henceforth, tive for research and therapeutics. simply PANIC) and joyful PLAY (neural sys- Many stressors used to evoke depres- tems are capitalized to highlight their prima- sive phenotypes—from physical to psycho-

Jaak Panksepp is affiliated with the Department of VCAPP, College of Veterinary Medicine, Washington State University, Pullman. Douglas Watt is with Cambridge City Hospital, Harvard Medical School, Cambridge, Mas- sachusetts. This work was supported by the for Depression Research Foundation to JP. Address correspondence to Jaak Panksepp, Department of VCAPP, College of Veterinary Medicine, Washington State University, Pullman, WA 99164-6351. E-mail: [email protected].

© 2011 Guilford Publications, Inc. 6 Why Does Depression Hurt?

logical (e.g., social-defeat in adult aggressive Depression research during the last encounters)—remain to be clearly linked four decades of the 20th century focused most to specific emotional network activities, al- heavily on the consequences of stress (DeK- though neuroanatomical correlates have loet, Joels, & Holsboer, 2005; McEwen, been identified (e.g., Kanarik et al., 2011). 2007) and brain norepinephrine and sero- Most animal models of depression not only tonin dynamics (from Schildkraut, 1965, to employ very general stressors but also gen- Harro & Oreland, 2001, so to speak). This eral behavioral outcome measures—various excellent work has largely neglected why de- timid behaviors and diminished re- pression feels so bad. It is becoming harder sponses (e.g., hopeless swimming patterns to believe that general brain serotonergic and diminished sexual eagerness). Rarely and/or noradrenergic changes, which glob- are specific emotional circuits prescribed as ally regulate aspects of forebrain arousal targets of analysis. Because of general stres- and dynamics, will specifically explain the sors and nonspecific outcome measures, such morbid moods of depression (Delgado et al., preclinical studies rarely provide insights 1990). These amines regulate quite general into psychodynamic or interpersonal consid- brain arousal functions that influence all erations of primary concern for clinical prac- . It is no that SSRIs mild- titioners, especially the of social loss ly ameliorate many psychiatric problems, and defeat that promote depressive affects. while having modest overall efficacy, as Modern neuroscience, especially as applied highlighted by disappointing STAR*D find- to animal models, has little room for discus- ings (, 2007; Rush, Trivedi, & Fava, sions of mental phenomena—especially the 2003). Likewise, more recent work on vari- affective experiences—that characterize psy- ous neurotrophic factor depletions (Koziek, chopathologies. Middlemas, & Bylund, 2008), stress-induced In line with Watt & Panksepp (2009) hippocampal shrinkage and CNS inflamma- and Solms & Panksepp (2011), we believe tion (Miller, Maletic, & Raison, 2009), and emotional-systems analyses will promote underlying genetics (Levinson, 2006), albeit better interdisciplinary dialog, yielding bet- of potential causal significance, provide little ter therapeutic interventions, where general understanding of the affective feelings that biogenic amine and cognitive-behavioral reg- characterize depression. Affective neurosci- ulatory strategies are commonly emphasized ence approaches can illuminate the subjec- more than affect-oriented therapies (but see tive manifestations of depressive affect (e.g., Fosha, Siegel, & Solomon, 2009, and Sh- Kroes et al., 2007; Panksepp, 2006; Pank- edler, 2010, for counter-examples). On the sepp et al., 2002.). psychopharmacological front, affective neu- roscience views promote the development An Affective Neuroscientific of new medicinals that target neuropeptide Perspective on Why systems, such as endogenous opioids (both Depression Feels so Bad mu and kappa varieties) and corticotrophin releasing factor (CRF) dynamics, as well as amino acid transmitters, such as glutamate In extending the original Bowlby ac- and glycine, that substantively control many count of depression to depression neurobiol- affective states, including emotional learn- ogy (Watt & Panksepp, 2009), we here focus ing. On the psychotherapeutic front, affec- on how brain affective networks, altered by tive neuroscience approaches promote better sustained distress, may explain the psycho- and more specific utilization of positive emo- logical pain and of depression. tions, such as facilitated SEEKING, CARE, Overactivity of brain separation-distress and PLAY dynamics, which currently remain PANIC/GRIEF and underactivity of SEEK- underdeveloped. ING networks may explain how the biggest Panksepp and Watt 7

Figure 1. Human and animal schematics of and separation-distress systems. Animal data comes from localized brain mapping of separation distress circuits in guinea pigs (Herman & Panksepp, 1981) and human data from Damasio, et al., 2000 (from Panksepp 2003). epidemiological stressor, namely social loss, the last two PANIC facilitators have yielded promotes depression (Bowlby, 1980; Heim promising effects (Holsboer, & Nemeroff, 1999). Depression may feel bad 2000; Zarate et al., 2006). Likewise, it is to because brain separation-distress systems be anticipated that opioid and oxytocin fa- create . As Bowlby recog- cilitators may alleviate depression. Indeed, nized, separation distress—the “protest” or opioids were widely used as “panic” responses that promptly follow so- before the modern era (Tenore, 2008), and cial loss, especially in young animals—feels ultra-lowdoses of buprenorphine are fine an- bad in a unique way. Affective understanding tidepressants for individuals not helped by of such brain processes, garnered by map- traditional (Bodkin et al., 1995). ping neuroanatomies and neurochemistries Perhaps oxytocinergic and prolactinergic of separation distress, helps clarify the na- drugs can be harnessed for similar ends. ture of social attachments and loss (Pank- sepp, 1998). These neuroanatomies are sum- But Separation Distress marized in Figure 1. is Only the Gateway to The PANIC/GRIEF circuitry starts in Depression midbrain central gray regions, commonly called the periaqueductal gray (PAG), and ascends through medial diencephalic struc- The PANIC/GRIEF system prob- tures, especially the dorsomedial , ably evolved from general pain mechanisms and terminates in various basal forebrain (Panksepp, 1998, 2003) presumably millions nuclei and subcallosal anterior cingulate of years ago (birds possess a homologous forebrain regions, which have been targeted system). This psychic-pain system promotes for (DBS) therapy for social cohesion, forges bonds between in- treatment-resistant depressions (Mayberg et fants and caretakers, and fortifies friendships al., 2005). Key neurochemistries that pro- and sexual relationships—in short, promotes mote separation calls (protest) are declining social solidarity among group living species. opioid and oxytocin chemistries and ele- Arousal of this system indexes social at- vated CRF, combined with increased gluta- tachments, reflecting how much one misses matergic drive in PANIC/GRIEF circuits of someone else. If someone is never missed, the brain. It is noteworthy that inhibitors of 8 Why Does Depression Hurt?

one does not have an attachment to that SEEKING urges, through low-dose facili- individual. The affective consequences of tation of mesolimbic DA arousal. Thus, in sustained arousal of this system are experi- the emergence of depressive affect, it is as enced as painful. This type of psychological important to emphasize the lassitude of di- , which most will avoid at minished SEEKING as the psychic pain of all costs, is a gateway to major forms of de- separation distress. Anisman and Matheson pression. (2005) found that stressors that promote The transition from protest, sadness, depressive profiles in animal models are ac- grief, and the like to depression proper is still companied by elevated thresholds in “brain poorly understood. One line of research sug- reward-SEEKING” arousal, which has been gests that immune modulators (e.g., cytokines replicated and extended by others (Nestler such as Interleukin 1, IL-6 and TNF-α) may & Carlezon, 2006; Pereira Do Carmo et al., stimulate the sustained despair of depression 2009). What causes this reduction in SEEK- (Hennessy, Deak, & Schiml-Webb, 2001). ING urges is a key question for depression re- Alternatively, perhaps sustained separation- search. A primary candidate is the gradually distress cascades into despair because of the increasing influence of dynorphins—power- ensuing diminution of SEEKING urges. We ful and pervasive brain opioids that mediate pursue this line of thought here. a very distinct form of negative affect that When protest fails to ensure recon- is recruited by social loss and demonstrably nection, a behavioral shutdown (depression) reduces the responsivity of the brain reward- comes into the picture to protect against the SEEKING system (McLaughlin et al., 2006). consequences of prolonged PANIC, leading Additional effects may come from increasing to diminished indices of active separation- pro-inflammatory cytokines (Miller et al., distress, but not fully diminished internal 2009). psychic pain. At this critical transition (from In sum, although negative affective the protest to the despair phase of separation changes in the opioid- and oxytocin-driven distress), a new form of sustained negative attachment and affectional systems may ini- affect, characterized by both lassitude and tiate depressive cascades–diminished SEEK- despair, sets in. This fully developed depres- ING may put “the nail in the coffin,” so to sive phenotype may arise when diminished speak. This scenario remains consistent with SEEKING activity attenuates the behavioral biogenic amine theories of depression, be- manifestations of protest. The further el- cause those general features of brain-mind evation of negative affect, contributed to by organization participate in the overall arous- “giving up” may yield a mixture of the sus- al level of all emotions animals exhibit. tained psychic pain of separation being inter- Because of the multidimensionality of mingled with the inability to recruit mental depression, there are bound to be many vari- energies such as SEEKING- that ants on these basic themes among the many characterizes positive “can-do” engagements subtypes of depression, including those with with the world and the pursuit of rewards, more or less residual grief (PANIC) type real or imagined. process, and differential degrees of SEEK- This giving-up, despair phase may ING system shutdown and . In the need to be counteracted not only by brain most common variant of depression, if psy- chemistries that reduce the psychic pain of chologically desirable outcomes from social loss but also by ways to override the down protest do not materialize and the psychic regulation of dopamine-driven SEEKING pain of separation-distress is prolonged, then urges that characterize depressive despair. additional shut-downs of positive feelings Low doses of opioid drugs can do both, promoted by diminished SEEKING urges yielding dopamine-independent feelings of change the acute negative affect into deep- satisfaction, as well as promoting dopamine- er and more prolonged phases of sustained Panksepp and Watt 9

negative despair. Although animal research will only discuss the antidepressant effects cannot illuminate the higher-order thought of moderate doses of the relatively safe opi- and rumination processes that characterize oid, buprenorphine. With regard to positive human depression, it can clarify the primal affective psychological approaches, we will mechanisms of negative affect. highlight the potential chemotherapeutic Beside the neurochemistry already consequences of playful interactions. highlighted, there will be many brain growth Before the modern era of psychop- factors and other neurochemical cascades harmacology, psychiatrists only had opioids that are bound to promote or retard this for treating mental suffering (Tenore, 2008). downward spiral (e.g., Feder, Nestler, & Although very effective as antidepressants in Charney, 2009). It is not only the goal of psy- the short-term, their addictive potential dis- chopharmacology to counteract and reverse couraged long-term use, even though with this downward cascade, but also of the psy- low prescription dosages of weak opioids, chotherapeutic disciplines. In our estimation, one could probably obtain sustained affec- new therapeutic approaches that promote the tive balance. Still, widespread addiction pho- positive hedonics of social CARE and PLAY bias have precluded full empirical evaluation systems may substantially improve thera- of such ideas. The mixed mu-opioid recep- peutic outcomes. Given how higher forms of tor agonist/antagonist buprenorphine solves human may be cognitive enhance- most (but probably not all) of these prob- ments of primary-process emotional systems lems, and open-trials have highlighted the for maternal CARE/NURTURANCE (Watt, high and sustained efficacy of low doses in 2007), promotion of these empathic systems depressed clients who received no relief from in psychotherapy may offer long-term pro- many traditional antidepressants (Bodkin et tection against depression and related con- al., 1995). This “miracle drug” (long off- ditions and may treat acute depression by patent) also has the uniquely desirable effect promoting reconnection and reattachment of blocking despair-promoting dynorphin of disconnected depressed individuals. receptors that are widespread in the brain and counteract the euphoric potentials of the general purpose reward-SEEKING system of New Psycho- the brain. Since high doses of buprenophine Chemotherapeutic block addictive mu-receptors, the drug has a Approaches fail-safe mechanism that limits addictive es- calations and the ensuing abuse and risk for In addition to the discovery of new uses respiratory depression/arrest of pure opiate for old chemistries--such as D-cycloserine, receptor stimulants. One reason this medi- an indirect glutamate facilitator--for the con- cation has been badly neglected in research solidation of psychotherapeutic outcomes in (e.g., there has been no proper follow-up of various disorders (e.g., Wilhelm et al., 2008), Bodkin and colleagues’ provocative work on we can now envision other beneficial mind- refractory depression) may be because of its brain influences from our emerging -under seriously diminished profit margin (it is off- standing of the primary-process social affec- patent). Without profits, who will conduct tive systems of the brain (Panksepp, 2011). It expensive clinical trials needed for medical is now clear that the brain changes and affec- approval in our materialistic society? tive mental imbalances in psychiatric disor- Likewise, the “power of PLAY” in ders are two-way neuropsychological streets. psychotherapy remains almost completely On the brain-chemistry-to-affective change untapped, at least in any systematic way. side, we can envision direct antidepressant There are good reasons to believe that re- effects with new positive-affect-promoting cruiting such mental energies could effective- chemistries. Because of limited space, we ly ameliorate various recalcitrant childhood 10 Why Does Depression Hurt?

problems, such as childhood depression and by chronic depressive despair. Affective neu- impulsivity (Panksepp, 2007); such pro-so- roscience research has provided abundant cial activities promote positive moods and data on the brain mechanisms of separation- brain maturation. Play promotes various distress (Panksepp, 1998), and hence the pro- growth factors such as BDNF in the brain test mechanisms that promote depression, by (Gordon et al., 2003), which has antidepres- gradually diminishing SEEKING that presag- sant effects, partly by opposing hippocampal es depressive despair. The separation-distress dysgenesis that often accompanies depres- mediating PANIC/GRIEF system is regulated sion (McEwen, 2007). Remarkably, animal by various prosocial neuropeptides that also models have yielded antidepressant-type hip- promote CARE and PLAY behaviors (e.g., pocampal neuronal proliferation as a result endogenous opioids, oxytocin, and prolac- of joyful playfulness, as indexed by happy- tin). The ability of these systems to consoli- playful “chirps” (Wöhr et al., 2009). Neural date social bonds (Panksepp, 1981, 1998) networks for these 50 kHz ultrasonic vocal- helps explain why depression is almost twice izations (USVs), especially abundant during as common in females than males—namely, the social play of rats, have been mapped to female brains, because of CARE urges, are in- arousal of mesolimbic dopamine-SEEKING trinsically more responsive to prosocial emo- networks; these chirpy USVs provide di- tions than male brains. rect readout of positive affective responses The pain of depression—arising most- (e.g., euphoric eagerness) that may directly ly from social loss and social defeat—may be counteract depressive affect (Burgdorf et the price we mammals pay for the evolution- al., 2007). Conversely, diminished chirping, ary advantages of social bonds that enrich our along with elevated 22 kHz complaints, can lives and promote procreation and survival. index depressive affect (Kroes et al., 2007). Although animal research cannot inform us These are the kinds of direct affective mea- of the complex cognitive-affective amalgams sures that need to be more widely imple- that emerge in humans during depression mented in preclinical work. (especially depressive ruminations and the The robust effects of play on cortical “darkening” of most cognitions), preclini- gene-expression patterns (Burgdorf et al., cal work can inform us of the evolutionarily 2010) have revealed other growth factors conserved affective mechanisms that lie at that may prove to be affectively positive ad- the very heart of depressive despair. juncts to playful psychotherapy. The largest The breadth and depth of our human gene-expression change we have seen is eleva- cognitive consciousness has been widened tion of Insulin Like Growth Factor-1 (IGF-1) enormously by the intellectual potentials of expression (Burgdorf et al., 2010). When our enlarged brains and the resulting cul- IGF-1 was evaluated for functional effects tural supports. But we remain inheritors of on relevant social behaviors, using direct in- ancient biological values that constitute the tracerebral injections of an IGF-1 receptor very ground of affective meaning within our antagonist, as well as siRNA inhibition of minds. Although this affective groundwork IGF-1 brain activity, convergent evidence for for existence is hard to speak about clearly, it elevated positive affect was obtained (Burg- is from within our ancient animalian nature, dorf et al., 2010). Further research on the full of primary-process affects, that the sub- positive social-affective chemistries of mam- jectively experienced blessings and curses of malian brains will surely yield new ways to our existence emerge. The primary-process promote feelings of secure well-being that /affect-generating systems are all can help counteract depressive cascades. situated in ancient medially located subcor- In sum, as Bowlby (1980) originally tical brain regions that all mammals share conjectured, depression arises from sustained from common ancestry. These primal pow- separation-distress that is eventually followed ers of the mind get connected to many life Panksepp and Watt 11

experiences through , but their affec- psychologically detached from the world. tive intensity is our mammalian evolutionary That sustained loss of psychological “ener- birthright. A comparative neurophenom- gy” and meaning may be intimately linked enology is critically important for unraveling to diminished SEEKING urges. The fact that the affective processes that make depression, such feelings can be easily provoked, and and many other emotional problems of the are difficult to erase, leading some individu- mind, affectively intense. Affective neurosci- als to heightened vulnerability to depression ence strategies have allowed us to envision and highly maladaptive behaviors, does not how John Bowlby’s seminal conceptual work contravene the biological forces that selected on the genesis of depression can finally be them into the mammalian genome in the first linked to specific affective networks that can place. Those forces center around the adap- be studied, in causal detail, only in animal tive nature of social connections (prerequi- models (Krishanan & Nestler, 2008; Pank- sites for separation distress) and the compet- sepp et al., 1991; Pryce et al., 2005). ing and equally compelling adaptive need to terminate the futility of protracted separa- tion distress, when it would either exhaust Discussion and Conclusions the protesting creature or serve as a beacon for predation. Agitated separation distress is normally shut down by a composite of So why does depression feel bad? It feels changes, including diminished dopamine bad, from our view, for two reasons, both arousal, declining mu and delta and increas- related to diminished feelings of internal se- ing kappa-opioids—dynorphins—and vari- curity: First, because of its intrinsic relation- ous inflammation-promoting cytokines. All ship to separation distress, which encourages these changes may prompt animals to “give us to form and maintain attachments, par- up”—to succumb to depressive despair. An ticularly to early caregiving figures, but also understanding of the affective brain may with our sexual mates and offspring and sup- eventually yield emotional endophenotypes portive social groups; and second, because that underlie psychiatric disorders (Pank- depression persuades us to give up hope if sepp, 2005, 2006), knowledge that can be our attempts to reunite with such figures or harnessed for therapeutic ends. groups do not succeed. Thereby, we become

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